Stress and Parkinson’s disease

April 26, 2017April 26, 2017 ~ Simon ~ 1 Comment

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Stress.

We all suffer it. Whether it is work related, relationship related, or simply self-induced, we humans foolishly put a great deal of pressure on our bodies.

Many pieces of research suggest that this pressure takes a toll on our health, which could lead to long-term conditions like Parkinson’s disease.

Recently some Korean researchers have identified a stress-related hormone that could have beneficial effects for Parkinson’s disease.

In today’s post, we will review their recently published research and look at what it means for people with Parkinson’s disease.

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Source: Islamicity

Shortly before leaving the role of President of the United States of America, ex-President Barrack Obama was asked about the stress that comes with the job, and his answer was interesting. He suggested that it is important to take a ‘long view’ of events and not to get bogged down by the weight of everything going on around you:

Despite these sage words, it is difficult not to notice the impact that his previous job has had on the man:

What a stress can do to a person. Source: Reddit

Stress seems to be a major part of modern life for many people – some people even indicate that they need it and that they thrive on it. But this pressure that we put on our bodies tends to have a damaging effect on our general health. And there is evidence that that stress may even lead to long term consequences such as cancer and neurodegenerative conditions such as Parkinson’s disease.

Causality, however, is very difficult to determine in science.

The best we can do is suggest that a particular variable (such as stress) may increase one’s risk of developing a particular condition (such as Parkinson’s disease).

So what do we know about stress and Parkinson’s disease?

This is Professor Bas Bloem.

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Prof Bloem – no stress here. Source: NRC

He’s awesome.

Professor Bloem is a consultant neurologist at the Department of Neurology, Radboud University Nijmegen Medical Centre (the Netherlands). He is also one of the researchers behind ParkinsonNet – an innovative healthcare concept that now consists of 64 professional networks for people with Parkinson’s disease covering all of the Netherlands.

In 2010, his research group noticed something interesting:

Bloem

Title: Artistic occupations are associated with a reduced risk of Parkinson’s disease.
Authors: Haaxma CA, Borm GF, van der Linden D, Kappelle AC, Bloem BR.
Journal: J Neurol. 2015 Sep;262(9):2171-6.
PMID: 26138540 (This article is OPEN ACCESS if you would like to read it)

In their study, Prof Bloem and his colleagues conducted a case–controlled analysis of 750 men with Parkinson’s disease (onset ≥40 years) and 1300 healthy men, which involved the participants completing a questionnaire about their occupational history. As expected (based on previous reports), they found that farming was associated with an increased risk of developing Parkinson’s disease (click here for more on this).

Interestingly, artistic occupations late in life were associated with a reduced risk of subsequent Parkinson’s disease. Another interesting observation from the study was that no initial occupation (early in life) predicted Parkinson’s disease, which the researchers proposed indicated that the premotor phase of the disease starts later in life.

One interpretation of this finding is that creative people are less likely to develop Parkinson’s disease. An alternative theory, however, may be that artist jobs are associated with a less stressful, more relaxed lifestyle.

Could it be that the lower levels of stress associated with artistic occupations may be having an impact on the risk of developing Parkinson’s disease?

This idea is not as crazy as it sounds.

Consider different kinds of stress. Research suggests that people who undergo tremendous emotional stress have a higher risk of developing Parkinson’s disease. For example, there is the case of ex-prisoners of war:

Prisoner

Title:Neurological disease in ex-Far-East prisoners of war
Authors: Gibberd FB, Simmonds JP.
Journal: Lancet. 1980 Jul 19;2(8186):135-7.
PMID: 6105303

At the end of World war II, a neurological unit was set up at Queen Mary’s Hospital (Roehampton) to treat Ex-Far East prisoners of war. 4684 individuals were referred to the unit, of these 679 were found to have neurological disease (most of these – 593 cases – were loss of sight and peripheral nerve damage).

In follow up work in the 1970s, however, it was found that many of these individuals had gone on to develop other neurological conditions (dementia, multiple sclerosis, etc). Of interest to us, though was the finding that across the entire group of ex-prisoners investigated (4684 individuals), Parkinson’s disease was apparent in 24 of them – this is a frequency 5x that of the general population!

Even in animal models of Parkinson’s disease, emotional stress seems to exaccerbate the neurodegeneration that is being modelled:

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Title: Stress accelerates neural degeneration and exaggerates motor symptoms in a rat model ofParkinson’s disease.
Authors: Smith LK, Jadavji NM, Colwell KL, Katrina Perehudoff S, Metz GA.
Journal: Eur J Neurosci. 2008 Apr;27(8):2133-46.
PMID: 18412632 (This article is OPEN ACCESS if you would like to read it)

The investigators in this study demonstrated that chronic stress exaggerates the motor/behavioural deficits in a rat model of Parkinson’s disease. In addition, the stress resulted in a greater loss of dopamine neurons in the brains of these rats.

For an interesting review of the effect of stress in Parkinson’s disease – Click here.

Interesting. So what did the Korean researchers – you mentioned above – find this week?

Something interesting.

This is Dr Yoon-Il Lee.

Lee

Source: Dgist

He’s a dude.

He is a senior research scientists at the Daegu Gyeongbuk Institute of Science and Technology (DGIST) in Daegu Metropolitan City, South Korea.

Recently, his group has collaborated with Professor Yunjong Lee’s research team published this research report:

Lee

Title: Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway inParkinson’s disease model
Authors: Ham S, Lee YI, Jo M, Kim H, Kang H, Jo A, Lee GH, Mo YJ, Park SC, Lee YS, Shin JH, Lee Y.
Journal: Sci Rep. 2017 Apr 3;7(1):525. doi: 10.1038/s41598-017-00614-w.
PMID: 28366931 (This article is OPEN ACCESS if you would like to read it)

Dr Lee and his colleagues began this study with cells were engineered to produce a bioluminescent signal when a gene called Parkin was activated. Parkin is a Parkinson’s associated gene as genetic mutations in this gene can result in carriers developing a juvenile-onset/early-onset form of Parkinson’s disease.

The researchers then conducted an enormous screening experiment to find agents that turn on the Parkin gene. They applied a library of 1172 FDA-approved drugs (from Selleck Chemicals) to these cells – one drug per cell culture – and looked at which cell cultures began to produce a bioluminescent signal. They found 5 drugs that not only made the cells bioluminescent, but also resulted in Parkin protein being produced at levels 2-3 times higher than normal. Those drugs were:

Deferasirox – an iron chelator (interesting considering our previous post)
Vorinostat – a cancer drug (for treating lymphoma)
Metformin – a diabetes medication
Clindamycin – an antibiotic
Hydrocortisone

Hydrocortisone produced the highest levels of Parkin (Interestingly, hydrocortisone also did not increase the activity of PERK, an indicator of endoplasmic reticulum stress, while the other drugs did).

What is Hydrocortisone?

Hydrocortisone is the name for the hormone ‘cortisol’ when supplied as a medication.

Ok, so what is cortisol?

Cortisol is a glucocorticoid (a type of hormone) produced from cholesterol by enzymes in the cortex of the adrenal gland, which sits on top of the kidneys. It is produced in response to stress (physical or emotional)

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The location of the adrenal glands. Source: Cancer

Cortisol helps us to deal with physical or emotional stress by reducing the activity of certain bodily functions – such as the immune system – so that the body can focus all of it’s energies toward dealing with the stress at hand.

Now generally, the functions of cortisol are supposed to be short-lived – long enough for the body to deal with the offending stressor and then levels go back to normal. But the normal levels of cortisol also fluctuate across the span of the day, with levels peaking around 8-9am:

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A graph of cortisol levels over the day. Source: HealthTap

Ok, so what did the Korean researchers do next?

Dr Lee and his colleagues gave the hydrocortisone drug to cell cultures which they then stressed (causing cell death). Hydrocortisone protected the cells from dying, and (importantly) it achieved this feat in a manner that was dependent on parkin activation. In cells that do not naturally have parkin, hydrocortisone was found to have no effect on cell survival.

Next the researchers treated mice with hydrocortisone before they then modelled Parkinson’s disease using the neurotoxin 6-OHDA. Hydrocortisone treatment resulted in approximate a two-fold increase in levels of parkin within particular areas of the brain. Without hydrocortisone treatment, the mice suffered the loss of approximately 45% of their dopamine neurons. Mice pre-treated with hydrocortisone, however, demonstrated enhanced dopamine neuron survival.

The researchers concluded that a sufficient physiological supply of hydrocortisone was required for protection of the brain, and that hydrocortisone treatment could be further tested as a means of maintaining high levels of parkin in the brain.

So what do we know about cortisol in Parkinson’s disease?

So this is where the story gets interesting;

Dobbs

Title: Cortisol is higher in parkinsonism and associated with gait deficit.
Authors: Charlett A, Dobbs RJ, Purkiss AG, Wright DJ, Peterson DW, Weller C, Dobbs SM.
Journal: Acta Neurol Scand. 1998 Feb;97(2):77-85.
PMID: 9517856

The researchers who conducted this study were interested in the role of cortisol in Parkinson’s disease. They measured cortisol levels in the blood of 96 subjects with Parkinson’s disease and 170 control subjects. They found that cortisol levels were 20% higher in the subjects with Parkinson’s disease, and that MAO-B inhibitor treatment for Parkinson’s (Selegiline) reduced cortisol levels.

And MAO-B inhibitors are not the only Parkinson’s medication associated with reduced levels of cortisol:

Muller

Title: Acute levodopa administration reduces cortisol release in patients with Parkinson’s disease.
Authors: Müller T, Welnic J, Muhlack S.
Journal: J Neural Transm (Vienna). 2007 Mar;114(3):347-50.
PMID: 16932991

In this study the researchers found that cortisol levels started to decrease significantly just 30 minutes after L-dopa was taken.

Whether this lowering of cortisol levels may have any kind of detrimental effect on Parkinson’s disease is yet to be determined and required further investigation.

Is hydrocortisone or cortisol used in the clinic?

Yes it is.

Hydrocortisone is used to treat rheumatism, skin diseases, and allergies.

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Hydrocortisone tablets. Source: Wisegeeks

Thus, there is the potential for another example of drug repurposing here. But the drug is not without side effects, which include:

Sleep problems (insomnia)
Mood changes
Acne, dry skin, thinning skin, bruising or discoloration;
Slow wound healing
Increased sweating
Headache, dizziness, spinning sensation;
nausea, stomach pain

For the full list of potential side effects – click here.

So what does it all mean?

Researchers in Korea have recently found that hydrocortisone (cortisol) can increase levels of Parkinson’s associated protein Parkin in cells, which in turn has a positive, neuroprotective effect on models of Parkinson’s disease.

We will now wait to see if the results can be independently replicated before attempting to take this drug to clinical trials for Parkinson’s disease. Any replication of the study should involve a range of treatment regimes so that we can determine if delayed administration can also be beneficial (this would involve delaying hydrocortisone treatment until after the neurotoxin has been given). Those studies could also look at the inflammatory effect in the brains as hydrocortisone has previously been demonstrated to have anti-inflammatory effects.

Interesting times. Stay tuned.

EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. While some of the drugs discussed on this website are clinically available, they may have serious side effects. We urge caution and professional consultation before altering any treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.

The banner for today’s post was sourced from ZetaYarwood

Iron, life force, and Parkinson’s disease

April 19, 2017July 3, 2017 ~ Simon ~ 5 Comments

pranaLogo

‘Prana’ is a Hindu Sanskrit word meaning “life force”.

An Australian biotech company has chosen this word for their name.

Recently Prana Biotechnology Ltd announced some exciting results from their Parkinson’s disease research programme.

In today’s post we will look at what the company is doing, the science underlying the business plan, and review the results they have so far.

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Source: ADPD2017

At the end of March, over 3000 researchers in the field of neurodegeneration gathered in the Austrian capital of Vienna for the 13th International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (also known as ADPD2017).

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The Vienna city hall. Source: EUtourists

A lot of interesting new research in the field of Parkinson’s disease was presented at the conference (we will look at some other presentation in future posts), but one was of particular interest to us here at SoPD HQ.

The poster entitled: ‘Abstract: 104 – PBT434 prevents neuronal loss, motor function and cognitive impairment in preclinical models of movement disorders by modulation of intracellular iron’, was presented by Associate Professor David Finkelstein, of the Florey Institute of Neuroscience and Mental Health (Melbourne, Australia).

Unfortunately the ADPD2017 conference’s scientific programme search engine does not allow for individual abstracts to be linked to on the web so if you would like to read the abstract, you will need to click here for the search engine page and search for ‘PBT434’ or ‘Finkelstein’ in the appropriate boxes.

Prof Finkelstein was presenting preclinical research that had been conducted by an Australian biotech company called Prana Biotechnology Ltd.

promo1

Source: Prana Biotechnology Ltd

What does the company do?

Prana Biotechnology Ltd has a large portfolio of over 1000 small chemical agents that they have termed ‘MPACs’ (or Metal Protein Attenuating Compounds). These compounds are designed to interrupt the interactions between particular metals and target proteins in the brain. The goal of this interruption is to prevent deterioration of brain cells in neurodegenerative conditions.

For Parkinson’s disease, the company is proposing a particular iron chelator they have called PBT434.

What is an iron chelator?

Iron chelator therapy involves the removal of excess iron from the body with special drugs. Chelate is from the Greek word ‘chela’ meaning “claw”.

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Chelator therapy. Source: Stanford

Iron overload in the body is a common medical problem, sometimes arising from disorders of increased iron absorption such as hereditary haemochromatosis. Iron chelator therapy represents one method of reducing the levels of iron in the body.

But why is iron overload a problem?

iron

Iron. Source: GlobalSpec

Good question. It involves the basic properties of iron.

Iron is a chemical element (symbol Fe). It has the atomic number 26 and by mass it is the most common element on Earth (it makes up much of Earth’s outer and inner core). It is absolutely essential for cellular life on this planet as it is involved with the interactions between proteins and enzymes, critical in the transport of oxygen, and required for the regulation of cell growth and differentiation.

So why then – as Rosalind asked in Shakespeare’s As You Like It – “can one desire too much of a good thing?”

Well, if you think back to high school chemistry class you may recall that there are these things called electrons. And if you have a really good memory, you will recall that the chemical hydrogen has one electron, while iron has 26 (hence the atomic number 26).

atoms

The electrons of iron and hydrogen. Source: Hypertonicblog

Iron has a really interesting property: it has the ability to either donate or take electrons. And this ability to mediate electron transfer is one of the reasons why iron is so important in the body.

Iron’s ability to donate and accept electrons means that when there is a lot of iron present it can inadvertently cause the production of free radicals. We have previously discussed free radicals (Click here for that post), but basically a free radical is an unstable molecule – unstable because they are missing electrons.

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How free radicals and antioxidants work. Source: h2miraclewater

In an unstable format, free radicals bounce all over the place, reacting quickly with other molecules, trying to capture the much needed electron to re-gain stability. Free radicals will literally attack the nearest stable molecule, to steal an electron. This leads to the “attacked” molecule becoming a free radical itself, and thus a chain reaction is started. Inside a living cell this can cause terrible damage, ultimately killing the cell.

Antioxidants can help try and restore the balance, but in the case of iron overload iron doctors will prescribe chelator treatment to deal with the situation more efficiently. By soaking up excess iron, we can limit the amount of damage caused by the surplus of iron.

So what research has been done regarding iron content and the Parkinsonian brain?

Actually, quite a lot.

In 1968, Dr Kenneth Earle used an X-ray based technique to examine the amount of iron in the substantia nigra of people with Parkinson’s disease (Source). The substantial nigra is one of the regions in the brain most badly damaged by the condition – it is where most of the brain’s dopamine neurones resided.

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The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp

Earle examined 11 samples and compared them to unknown number of control samples and his results were a little startling:

The concentration of iron in Parkinsonian samples was two times higher than that of the control samples.

Since that first study, approximately 30 investigations have been made into levels of iron in the Parkinsonian brain. Eleven of those studies have replicated the Earle study by looking at postmortem tissue. They have used different techniques and the results have varied somewhat:

Sofic et al. (1988) 1.8x increase in iron levels
Dexter et al. (1989) 1.3x increase in iron levels
Uitti et al. (1989) 1.1x increase in iron levels
Riederer et al 1989 1.3x increase in iron levels
Griffiths and Crossman (1993) 2.0x increase in iron levels
Mann et al. (1994) 1.6x increase in iron levels
Loeffler et al. (1995) 0.9 (lower)
Galazka-Friedman et al., 1996 1.0 (no difference)
Wypijewska et al. (2010) 1.0 (no difference)
Visanji et al, 2013 1.7x increase in iron levels

Overall, however, there does appear to be a trend in the direction of higher levels of iron in the Parkinsonian brains. A recent meta-analysis of all this data confirmed this assessment as well as noting an increase in the caudate putamen (the region of the brain where the dopamine neuron branches release their dopamine – Click here for that study).

Brain imaging of iron (using transcranial sonography and magnetic resonance imaging (MRI)) has also demonstrated a strong correlation between iron levels in the substantia nigra region and Parkinson’s disease severity/duration (Click here and here to read more on this).

Thus, there appears to be an increase of iron in the regions most affected by Parkinson’s disease and this finding has lead researchers to ask whether reducing this increase in iron may help in the treatment of Parkinson’s disease.

How could iron overload be bad in Parkinson’s disease?

Well in addition to causing the production of free radicals, there are many possible ways in which iron accumulation could be aggravating cell loss in Parkinson’s disease.

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Possible causes and consequences of iron overload in Parkinson’s disease. Source: Hindawi

High levels of iron can cause the oxidation of dopamine, which results in the production of hydrogen peroxide (H₂O₂– a reactive oxygen species – the stuff that is used to bleach hair and is also used as a propellant in rocketry!). This reaction can cause further oxidative stress that can then lead to a range of consequences including protein misfolding, lipid peroxidation (which can cause the accumulation of the Parkinson’s associated protein alpha synuclein), mitochondrial dysfunction, and activation of immune cells in the brain.

And this is just a taster of the consequences.

For further reading on this topic we recommend two very good reviews – click here and here.

Ok, so iron overload is bad, but what was the research presented in Austria?

The abstract:

Title: PBT434 prevents neuronal loss, motor function and cognitive impairment in preclinical models of movement disorders by modulation of intracellular iron
Authors: D. Finkelstein, P. Adlard, E. Gautier, J. Parsons, P. Huggins, K. Barnham, R. Cherny
Location: C01.a Posters – Theme C – Alpha-Synucleinopathies

The researchers at Prana Biotechnology Ltd assessed the potential of one of their candidate drugs, PBT434, in both cell culture and animal models of Parkinson’s disease. The PBT434 drug was selected for further investigation based on its performance in cell culture assays designed to test the inhibition of oxidative stress and iron-mediated aggregation of Parkinson’s associated proteins like alpha synuclein.

PBT434 significantly reduced the accumulation of alpha synuclein and markers of oxidative stress, and prevented neuronal loss.

The investigators also demonstrated that orally administered PBT434 readily crossed the blood brain barrier and entered the brain. In addition the drug was well-tolerated in the experimental animals and improved motor function in toxin-induced (MPTP and 6-hydroxydopamine) and transgenic mouse models of Parkinson’s disease (alpha synuclein -A53T and tau – rTg4510).

These results are in agreement with previous studies that have looked at iron chelator therapy in models of Parkinson’s disease (Click here, here and here for some examples)

Interestingly, PBT434 also demonstrated neuroprotective properties in animal models of multiple systems atrophy (or MSA). Suggesting that perhaps iron chelation could be a broad neuroprotective approach.

The researchers concluded that this preclinical data demonstrates the efficacy of PBT434 as a clinical candidate for Parkinson’s disease. PBT434 shows a strong toxicology profile and favourable therapeutic activity. Prana is preparing its pre-clinical development package for PBT434 to initiate human clinical trials.

Does Prana have any other drugs in clinical trials?

Yes, they do.

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Source: Prana

Prana Biotechnology has another product called PBT2.

The company currently has two clinical trial programs for PBT2 focused on two other neurodegenerative diseases: Alzheimer’s disease and Huntington’s disease.

The Alzheimer’s study was called the IMAGINE Trial, but (there is always a ‘but’) recently PBT2 failed to meet its primary endpoint (significantly reducing levels of beta-amyloid – the perceived bad guy in Alzheimer’s disease) in a phase III trial of mild Alzheimer’s disease. PBT2 was, however, shown to be safe and very well tolerated over the 52 week trial, with no difference in the occurrence of adverse events between the placebo and treated groups.

In addition, there was less atrophy (shrinkage) in the brains of those patients treated with PBT2 when compared to control brains, 2.6% and 4.0%, respectively (based on brain imaging). The company is tracking measures of brain volume and cognition in a 12 month extension study. It could be interesting to continue that follow up long term to evaluate the consequences of long term use of this drug on Alzheimer’s disease – even if the effect is minimal, any drug that can slow the disease down is useful and could be used in conjunction with other neuroprotective medications.

For Huntington’s disease, the company is also using the PBT2 drug and this study has had a bit more success. The study, called Reach2HD, was a six month phase II clinical trial in 109 patients with early to mid-stage Huntington’s disease, across 20 sites in the US and Australia. The company was aiming to assess the safety profile of this drug in this particular condition, as well as determining the motor and behavioural benefits.

In the ReachHD study, PBT2 showed signs of improving some aspects of cognitive function in the study, which potentially represents a major event for a disease for which there is very little in the way of medical treatments.

For a full description of the PBT2 trials, see this wikipedia page on the topic.

Is Prana the only research group working on iron chelators technology for Parkinson’s disease?

No.

There is a large EU-based consortium called FAIR PARK II, which is running a five year trial (2015 – 2020) of the iron chelator deferiprone (also known as Ferriprox). The study is a multi-centre, placebo-controlled, randomised clinical trial involving 338 people with recently diagnosed Parkinson’s disease.

LOGO_FAIR_PARK_TIME1

The population will be divided into two group (169 subjects each). They will then be assigned either deferiprone (15 mg/kg twice a day) or a placebo. Each subject will be given 9-months of treatment followed by a 1-month post-treatment monitoring period, in order to assess the disease-modifying effect of deferiprone (versus placebo).

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Deferiprone. Source: SGPharma

As far as we are aware, this FAIR PARK II clinical trial is still recruiting participants – please click here to read more about this – thus it will most likely be some time before we hear the results of this study.

Are there natural sources of chelators?

Yes there are. In fact, many natural antioxidants exert some chelating activities.

Prominent among the natural sources of chelators: Green tea has components of plant extracts, such as epigallocatechin gallate (EGCG – which we have previously discussed in regards to Parkinson’s disease, click here to read that post) which possess structures which infer metal chelating properties.

As we have said before people, drink more green tea!

cup and teapot of linden tea and flowers isolated on white

Anyone fancy a cuppa? Source: Expertrain

So what does it all mean?

Summing up: We do not know what causes Parkinson’s disease. Most of our experimental treatments are focused on the biological events that occur in the brain around and after the time of diagnosis. These include an apparent accumulation of iron in affected brain regions.

Research groups are currently experimenting with drugs that reduce the levels of iron in the brain as a potential treatment for Parkinson’s disease. Preclinical data certainly look positive. We will now have to wait and see if those results translate into the human.

Previous clinical trials of metal chelators in neurodegeneration have had mixed success in demonstrating positive benefits. It may well be, however, that this treatment approach should be used in conjunction with other neuroprotective approaches – as a supplement. It will be interesting to see how Prana Biotechnology’s drug PBT434 fares in human clinical trials for Parkinson’s disease.

Stay tuned for more on this.

UPDATE – 3rd May 2017

Today the results of a double-blind, phase II clinical trial of iron chelator deferiprone in Parkinson’s disease were published. The results of the study indicate a mildly positive effect (though not statistically significant) after 6 months of daily treatment.

Iron1
Title: Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease
Authors: Martin-Bastida A, Ward RJ, Newbould R, Piccini P, Sharp D, Kabba C, Patel MC, Spino M, Connelly J, Tricta F, Crichton RR & Dexter DT
Journal: Scientific Reports (2017), 7, 1398.
PMID: 28469157 (This article is OPEN ACCESS if you would like to read it)

In this Phase 2 randomised, double-blinded, placebo controlled clinical trial, the researchers recruited 22 people with early stage Parkinson’s disease (disease duration of less than 5 years; 12 males and 10 females; aged 50–75 years). They were randomly assigned to either a placebo group (8 participants), or one of two deferiprone treated groups: 20 mg/kg per day (7 participants) or 30 mg/kg per day (7 participants). The treatment was two daily oral doses (taken morning and evening), and administered for 6 months with neurological examinations, brain imaging and blood sample collections being conducted at 0, 3 and 6 months.

Deferiprone therapy was well tolerated and brain imaging indicated clearance of iron from various parts of the brain in the treatment group compared to the placebo group. Interestingly, the 30 mg/kg deferiprone treated group demonstrated a trend for improvement in motor-UPDRS scores and quality of life (although this was not statistically significance). The researchers concluded that “more extensive clinical trials into the potential benefits of iron chelation in PD”.

Given the size of the groups (7 people) and the length of the treatment period (only 6 months) in this study it is not really a surprise that the researchers did not see a major effect. That said, it is very intriguing that they did see a trend towards motor score benefits in the 30 mg/kg deferiprone group – remembering that this is a double blind study (so even the investigators were blind as to which group the subjects were in).

We will now wait to see what the FAIR PARK II clinical trial finds.

UPDATE: 28th June 2017

Today, the research that Prana biotechnology Ltd was presenting in Vienna earlier this year was published:

Prana

Title: The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease.
Authors: Finkelstein DI, Billings JL, Adlard PA, Ayton S, Sedjahtera A, Masters CL, Wilkins S, Shackleford DM, Charman SA, Bal W, Zawisza IA, Kurowska E, Gundlach AL, Ma S, Bush AI, Hare DJ, Doble PA, Crawford S, Gautier EC, Parsons J, Huggins P, Barnham KJ, Cherny RA.
Journal: Acta Neuropathol Commun. 2017 Jun 28;5(1):53.
PMID: 28659169 (This article is OPEN ACCESS if you would like to read it)

The results suggest that PBT434 is far less potent than deferiprone or deferoxamine at lowering cellular iron levels, but this weakness is compensated by the reduced levels of alpha synuclein accumulation in models of Parkinson’s disease. PBT434 certainly appears to be neuroprotective demonstrating improvements in motor function, neuropathology and biochemical markers of disease state in three different animal models of Parkinson’s disease.

The researchers provide little information as to when the company will be exploring clinical trials for this drug, but in the press release associated with the publication, Dr David Stamler (Prana’s Chief Medical Officer and Senior Vice President, Clinical Development) was quoted saying that they “are eager to begin clinical testing of PBT434”. We’ll keep an eye to the ground for any further news.

FULL DISCLOSURE: Prana Biotechnology Ltd is an Australasian biotechnology company that is publicly listed on the ASX. The information presented here is for educational purposes. Under no circumstances should investment decisions be made based on the information provided here. The SoPD website has no financial or beneficial connection to either company. We have not been approached/contacted by the company to produce this post, nor have we alerted them to its production. We are simply presenting this information here as we thought the science of what the company is doing might be of interest to other readers.

In addition, under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. Metal chelators are clinically available medications, but it is not without side effects (for more on this, see this website). We urge caution and professional consultation before altering a treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.

The banner for today’s post was sourced from Prana

On astrocytes and neurons – reprogramming for Parkinson’s

April 18, 2017April 19, 2017 ~ Simon ~ 13 Comments

NG2+-flare

Last week scientists in Sweden published research demonstrating a method by which the supportive cells of the brain (called astrocytes) can be re-programmed into dopamine neurons… in the brain of a live animal!

It was a really impressive trick and it could have major implications for Parkinson’s disease.

In today’s post is a long read, but in it we will review the research leading up to the study, explain the science behind the impressive feat, and discuss where things go from here.

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Different types of cells in the body. Source: Dreamstime

In your body at this present moment in time, there is approximately 40 trillion cells (Source).

The vast majority of those cells have developed into mature types of cell and they are undertaking very specific functions. Muscle cells, heart cells, brain cells – all working together in order to keep you vertical and ticking.

Now, once upon a time we believed that the maturation (or the more technical term: differentiation) of a cell was a one-way street. That is to say, once a cell became what it was destined to become, there was no going back. This was biological dogma.

Then a guy in Japan did something rather amazing.

Who is he and what did he do?

This is Prof Shinya Yamanaka:

yamanaka-s

Prof Shinya Yamanaka. Source: Glastone Institute

He’s a rockstar in the scientific research community.

Prof Yamanaka is the director of Center for induced Pluripotent Stem Cell Research and Application (CiRA); and a professor at the Institute for Frontier Medical Sciences at Kyoto University.

But more importantly, in 2006 he published a research report demonstrating how someone could take a skin cell and re-program it so that was now a stem cell – capable of becoming any kind of cell in the body.

Here’s the study:

IPS2

Title: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
Authors: Takahashi K, Yamanaka S.
Journal: Cell. 2006 Aug 25;126(4):663-76.
PMID: 16904174 (This article is OPEN ACCESS if you would like to read it)

Shinya Yamanaka‘s team started with the hypothesis that genes which are important to the maintenance of embryonic stem cells (the cells that give rise to all cells in the body) might also be able to cause an embryonic state in mature adult cells. They selected twenty-four genes that had been previously identified as important in embryonic stem cells to test this idea. They used re-engineered retroviruses to deliver these genes to mouse skin cells. The retroviruses were emptied of all their disease causing properties, and could thus function as very efficient biological delivery systems.

The skin cells were engineered so that only cells in which reactivation of the embryonic stem cells-associated gene, Fbx15, would survive the testing process. If Fbx15 was not turned on in the cells, they would die. When the researchers infected the cells with all twenty-four embryonic stem cells genes, remarkably some of the cells survived and began to divide like stem cells.

In order to identify the genes necessary for the reprogramming, the researchers began removing one gene at a time from the pool of twenty-four. Through this process, they were able to narrow down the most effective genes to just four: Oct4, Sox2, cMyc, and Klf4, which became known as the Yamanaka factors.

This new type of cell is called an induced pluripotent stem (IPS) cell – ‘pluripotent’ meaning capable of any fate.

The discovery of IPS cells turned biological dogma on it’s head.

And in acknowledgement of this amazing bit of research, in 2012 Prof Yamanaka and Prof John Gurdon (University of Cambridge) were awarded the Nobel prize for Physiology and Medicine for the discovery that mature cells can be converted back to stem cells.

Prof Yamanaka and Prof Gurdon. Source: UCSF

Prof Gurdon achieved the feat in 1962 when he removed the nucleus of a fertilised frog egg cell and replaced it with the nucleus of a cell taken from a tadpole’s intestine. The modified egg cell then grew into an adult frog! This fascinating research proved that the mature cell still contained the genetic information needed to form all types of cells.

EDITOR’S NOTE: We do not want to be accused of taking anything away from Prof Gurdon’s contribution to this field (which was great!) by not mentioning his efforts here. For the sake of saving time and space, we are focusing on Prof Yamanaka’s research as it is more directly related to today’s post.

ips-cells

Making IPS cells. Source: learn.genetics

This amazing discovery has opened new doors for biological research and provided us with incredible opportunities for therapeutic treatments. For example, we can now take skins cells from a person with Parkinson’s disease and turn those cells into dopamine neurons which can then be tested with various drugs to see which treatment is most effective for that particular person (personalised medicine in it’s purest form).

nature10761-f2.2

Some of the option available to Parkinson’s disease. Source: Nature

Imagination is literally the only limiting factor with regards to the possible uses of IPS cell technology.

Shortly after Yamanaka’s research was published in 2006, however, the question was asked ‘rather than going back to a primitive state, can we simply change the fate of a mature cell directly?’ For example, turn a skin cell into a neuron.

This question was raised mainly to address the issue of ‘age’ in the modelling disease using IPS cells. Researchers questioned whether an aged mature cell reprogrammed into an immature IPS cell still carried the characteristics of an aged cell (and can be used to model diseases of the aged), or would we have to wait for the new cell to age before we can run experiments on it. Skin biopsies taken from aged people with neurodegenerative conditions may lose the ‘age’ element of the cell and thus an important part of the personalised medicine concept would be lost.

So researchers began trying to ‘re-program’ mature cells. Taking a skin cell and turning it directly into a heart cell or a brain cell.

And this is probably the craziest part of this whole post because they actually did it!

Different methods of inducing skin cells to become something else. Source: Neuron

In 2010, scientists from Stanford University published this report:

Nature2

Title: Direct conversion of fibroblasts to functional neurons by defined factors
Authors: Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M.
Journal: Nature. 2010 Feb 25;463(7284):1035-41.
PMID: 20107439

In this study, the researchers demonstrated that the activation of three genes (Ascl1, Brn2 and Myt1l) was sufficient to rapidly and efficiently convert skin cells into functional neurons in cell culture. They called them ‘iN’ cells’ or induced neuron cells. The ‘re-programmed’ skin cells made neurons that produced many neuron-specific proteins, generated action potentials (the electrical signal that transmits a signal across a neuron), and formed functional connection (or synapses) with neighbouring cells. It was a pretty impressive achievement, which they beat one year later by converting mature liver cells into neurons – Click here to read more on this – Wow!

The next step – with regards to our Parkinson’s-related interests – was to convert skin cells directly into dopamine neurons (the cells most severely affected in the condition).

And guess what:

PSNA

Title: Direct conversion of human fibroblasts to dopaminergic neurons.
Authors: Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Björklund A, Lindvall O, Jakobsson J, Parmar M
Journal: Proc Natl Acad Sci U S A (2011) 108:10343-10348.
PMID: 21646515 (This article is OPEN ACCESS if you would like to read it)

In this study, Swedish researchers confirmed that activation of Ascl1, Brn2, and Myt1l re-programmed human skin cells directly into functional neurons. But then if they added the activation of two additional genes, Lmx1a andFoxA2 (which are both involved in dopamine neuron generation), they could convert skin cells directly into dopamine neurons. And those dopamine neurons displayed all of the correct features of normal dopamine neurons.

With the publication of this research, it suddenly seemed like anything was possible and people began make all kinds of cell types out of skin cells. For a good review on making neurons out of skin cells – Click here.

Given that all of this was possible in a cell culture dish, some researchers started wondering if direct reprogramming was possible in the body. So they tried.

And again, guess what:

Nature1

Title: In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.
Authors: Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA.
Journal: Nature. 2008 Oct 2;455(7213):627-32.
PMID: 18754011

Using the activation of three genes (Ngn3, Pdx1 and Mafa), the investigators behind this study re-programmed differentiated pancreatic exocrine cells in adult mice into cells that closely resemble b-cells. And all of this occurred inside the animals, while the animals were wandering around & doing their thing!

Now naturally, researchers in the Parkinson’s disease community began wondering if this could also be achieved in the brain, with dopamine neurons being produced from re-programmed cells.

And (yet again) guess what:

in-vivo

Title: Generation of induced neurons via direct conversion in vivo
Authors: Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S, Jakobsson J, Björklund A, Grealish S, Parmar M.
Journal: Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):7038-43.
PMID: 23530235 (This article is OPEN ACCESS if you would like to read it)

In this study, the Swedish scientists (behind the previous direct re-programming of skin cells into dopamine neurons) wanted to determine if they could re-program cells inside the brain. Firstly, they engineered skin cells with the three genes (Ascl1, Brn2a, & Myt1l) under the control of a special chemical – only in the presence of the chemical, the genes would be activated. They next transplanted these skin cells into the brains of mice and began adding the chemical to the drinking water of the mice. At 1 & 3 months after transplantation, the investigators found re-programmed cells inside the brains of the mice.

Next, the researchers improved on their recipe for producing dopamine neurons by adding the activation of two further genes: Otx2 and Lmx1b (also important in the development of dopamine neurons). So they were now activating a lot of genes: Ascl1, Brn2a, Myt1l, Lmx1a, FoxA2, Otx2 and Lmx1b. Unfortunately, when these reprogrammed cells were transplanted into the brain, few of them survived to become mature dopamine neurons.

The investigators then ask themselves ‘do we really need to transplant cells? Can’t we just reprogram cells inside the brain?’ And this is exactly what they did! They injected the viruses that allow for reprogramming directly into the brains of mice. The experiment was designed so that the cargo of the viruses would only become active in the astrocyte cells, not neurons. And when the researchers looked in the brains of these mice 6 weeks later, they found numerous re-programmed neurons, indicating that direct reprogramming is possible in the intact brain.

So what was so special about the research published last week about? Why the media hype?

The research published last week, by another Swedish group, took this whole process one step further: Not only did they re-program astrocytes in the brain to become dopamine neurons, but they also did this on a large enough scale to correct the motor issues in a mouse model of Parkinson’s disease.

Here is the study:

Title: Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model
Authors: di Val Cervo PR, Romanov RA, Spigolon G, Masini D, Martín-Montañez E, Toledo EM, La Manno G, Feyder M, Pifl C, Ng YH, Sánchez SP, Linnarsson S, Wernig M, Harkany T, Fisone G, Arenas E.
Journal: Nature Biotechnology (2017) doi:10.1038/nbt.3835
PMID: 28398344

These researchers began this project 6 years ago with a new cocktail of genes for reprogramming cells to become dopamine neurons. They used the activation of NEUROD1, ASCL1 and LMX1A, and a microRNA miR218 (microRNAs are genes that produce RNA, but not protein – click here for more on this). These genes improved the reprogramming efficiency of human astrocytes to 16% (that is the percentage of astrocytes that were infected with the viruses and went on to became dopamine neurons). The researchers then added some chemicals to the reprogramming process that helps dopamine neurons to develop in normal conditions, and they observed an increase in the level of reprogramming to approx. 30%. And these reprogrammed cells display many of the correct properties of dopamine neurons.

Next the investigators decided to try this conversion inside the brains of mice that had Parkinson’s disease modelled in them (using a neurotoxin). The delivery of the viruses into the brains of these mice resulted in reprogrammed dopamine neurons beginning to appear, and 13 weeks after the viruses were delivered, the researchers observed improvements in the Parkinson’s disease related motor symptoms of the mice. The scientists concluded that with further optimisation, this reprogramming approach may enable clinical therapies for Parkinson’s disease, by the delivery of genes rather than transplanted cells.

How does this reprogramming work?

As we have indicated above, the re-programming utilises re-engineered viruses. They have been emptied of their disease causing elements, allowing us to use them as very efficient biological delivery systems. Importantly, retroviruses infect dividing cells and integrate their ‘cargo’ into the host cell’s DNA.

RetroviralIntegration

Retroviral infection and intergration into DNA. Source: Evolution-Biology

The ‘cargo’ in the case of IPS cells, is a copy of the genes that allow reprogramming (such as the Yamanaka genes), which the cell will then start to activate, resulting in the production of protein for those genes. These proteins subsequently go on to activate a variety of genes required for the maintenance of embryonic stem cells (and re-programming of mature cells).

And viruses were also used for the re-programming work in the brain as well.

There is the possibility that one day we will be able to do this without viruses – in 2013, researchers made IPS cells using a specific combination of chemicals (Click here to read more about this) – but at the moment, viruses are the most efficient biological targeting tool we have.

So what does it all mean?

Last week researchers is Sweden published research explaining how they reprogrammed some of the helper cells in the brains of Parkinsonian mice so that they turned into dopamine neurons and helped to alleviate the symptoms the mice were feeling.

This result and the trail of additional results outlined above may one day be looked back upon as the starting point for a whole new way of treating disease and injury to particular organs in the body. Suddenly we have the possibility of re-programming cells in our body to under take a new functions to help combat many of the conditions we suffer.

It is important to appreciate, however, that the application of this technology is still a long way from entering the clinic (a great deal of optimisation is required). But the fact that it is possible and that we can do it, raises hope of more powerful medical therapies for future generations.

As the researchers themselves admit, this technology is still a long way from the clinic. Improving the efficiency of the technique (both the infection of the cells and the reprogramming) will be required as we move down this new road. In addition, we will need to evaluate the long-term consequences of removing support cells (astrocytes) from the carefully balanced system that is the brain. Future innovations, however, may allow us to re-program stronger, more disease-resistant dopamine neurons which could correct the motor symptoms of Parkinson’s disease without being affected by the disease itself (as may be the case in transplanted cells – click here to read more about this).

Watch for a lot more research coming from this topic.

The banner for today’s post was sourced from Greg Dunn (we love his work!)

An Ambroxol update – active in the brain

April 16, 2017 ~ Simon ~ 5 Comments

Ambroxol-800x400

This week pre-clinical data was published demonstrating that the Ambroxol is active in the brain.

This is important data given that there is currently a clinical trial being conducted for Ambroxol in Parkinson’s disease.

Today’s post will review the new data and discuss what is happening regarding the clinical trial.

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Ambroxol. Source: Skinflint

We have previously discussed the potential use of Ambroxol in the treatment of Parkinson’s disease (Click here to read that post). Today we follow up that post with new data that provides further support for an on-going clinical trial.

Firstly, what is Ambroxol?

Ambroxol is a commonly used treatment for respiratory diseases (the respiratory system being the lungs and related components required for breathing). Ambroxol promotes the clearance of mucus and eases coughing. It also has anti-inflammatory properties, reducing redness in a sore throat. It is the active ingredient of products like Mucosolvan, Mucobrox, and Mucol.

What is the connection between Ambroxol and Parkinson’s disease?

So this is where a gene called GBA comes into the picture.

Genetic mutations in the GBA (full name: Glucosylceramidase Beta) gene are the most common genetic anomaly associated with Parkinson’s disease. People with a mutation in their GBA gene have a higher risk of developing Parkinson’s disease than the general population. And interestingly, people with Parkinson’s disease are approximately five times more likely to carry a GBA mutation than healthy control subjects.

What does GBA do?

The GBA gene provides the instructions for making an enzyme (called glucocerebrosidase) that helps with the digestion and recycling of waste inside cells. The enzyme is located and active inside ‘lysosomes‘.

What are Lysosomes?

Lysosomes are small bags of digestive enzymes that can be found inside cells. They help to break down proteins that have either been brought into the cell or that have served their function and need to be digested and disposed of (or recycled).

Lysosomes

How lysosomes work. Source: Prezi

Inside the lysosomes are enzymes like glucocerebrosidase which help to break material down into useful parts. The lysosome will fuse with other small bags (called vacuole) that act as storage vessels of material inside a cell. The enzymes from the lysosome will mix with the material in the vacuole and digest it (or it break down into more manageable components).

Now people with a genetic mutation in their GBA gene will often have an abnormally short, non-functioning version of the glucocerebrosidase enzyme. In those cases the breaking down of waste inside the lysosome becomes inhibited. And if waste can’t be disposed of or recycled properly, things start to go wrong in the cell.

How does Ambroxol correct this?

It was recently shown that Ambroxol triggers exocytosis of lysosomes (Source). Exocytosis is the process by which waste is exported out of the cell.

exocytosis

Exocytosis. Source: Socratic

Thus by encouraging lysosomes to undergo exocytosis and spit their contents out of the cell – digested or not – Ambroxol allows the cell to remove waste effectively and therefore function in a more normal fashion. This mechanism of treatment seemingly bi-passes the faulty glucocerebrosidase digestion enzyme entirely.

Until recently, two important questions, however, have remained unanswered:

Does Ambroxol enter the brain and have this function there?
What are the consequences of long term Ambroxol use?

We now have an answer for question no. 1:

Amb2

Title: Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice.
Authors: Migdalska-Richards A, Daly L, Bezard E, Schapira AH.
Journal: Ann Neurol. 2016 Nov;80(5):766-775.
PMID: 27859541 (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers treated mice with Ambroxol for 12 days and then measured the level of glucocerebrosidase activity in the brain. They gave Ambroxol to three different groups of mice:

a group of normal mice,
a group of mice which had been genetically engineered with a specific mutation in their GBA gene (the heterozygous L444P mutation)
a group of mice that produced human alpha synuclein (the protein closely associated with Parkinson’s disease).

When they looked at the level of glucocerebrosidase enzyme activity in normal mice, they found an increase of approximately 20% (in mice treated with 4mM Ambroxol). One curious finding was that this dose was the only dose that increase glucocerebrosidase activity (1, 3, and 5mM of Ambroxol had no effect). The investigators noted, however, a reduction in water drinking of mice receiving 5mM in their drinking water (maybe they didn’t like the taste of it!), suggesting that they were not getting as much Ambroxol as the 4mM group.

The 4mM level of of Ambroxol also increased glucocerebrosidase activity in the L444P mutation mice and the alpha-synuclein mice (which interestingly also has reduced levels of glucocerebrosidase activity). One important observation in the alpha synuclein mice was the finding that Ambroxol was able to reduce the levels of alpha synuclein in the cells, indicating better clearance of un-wanted excess of proteins.

These combined results suggested to the investigators that Ambroxol is entering the brain of mice (passing through the protective blood brain barrier) and able to be effective there. In addition, they did not witness any serious adverse effects of ambroxol administration in the mice – an observation made in other studies of Ambroxol in normal mice (Click here to read more about this).

These studies have been followed up by a dosing study in primates which was just published:

Ambrox

Title: Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate.
Authors: Migdalska-Richards A, Ko WK, Li Q, Bezard E, Schapira AH.
Journal: Synapse. 2017 Mar 12. doi: 10.1002/syn.21967.
PMID: 28295625 (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators analysed the effect of Ambroxol treatment on glucocerebrosidase activity in three healthy non-human primates. One subject was given an ineffective control solution vehicle, another subject received 22.5 mg/day of Ambroxol and the third subject received 100 mg/day of Ambroxol. They showed that daily administration 100 mg/day of Ambroxol results in increased levels of glucocerebrosidase activity in the brain (approximately 20% increase on average across different areas of the brain). Importantly, the 22.5 mg treatment did not result in any increase.

The investigators wanted to determine if the effect of Ambroxol was specific to glucocerebrosidase, and so they analysed the activity of another lysosome enzyme called beta-hexosaminidase (HEXB). They found that 100 mg/day of Ambroxol also increased HEXB activity (again by approximately 20%), suggesting that Ambroxol may be having an effect on other lysosome enzymes and not just glucocerebrosidase.

The researches concluded that these results provide the first data of the effect of Ambroxol treatment on glucocerebrosidase activity in the brain of non-human primates. In addition, the results indicate that Ambroxol is active and as the researchers wrote “should be further investigated in the context of clinical trials as a potential treatment for Parkinson’s disease”.

And there is a clinical trial currently underway?

Yes indeed.

Funded by the Cure Parkinson’s Trust and the Van Andel Research Institute (USA), there is currently a phase I clinical trial with 20 people with Parkinson’s disease receiving Ambroxol over 24 months. Importantly, the participants being enrolled in the study have both Parkinson’s disease and a mutation in their GBA gene. The study is being led by Professor Anthony Schapira at the Royal Free Hospital (London).

EDITORS NOTE HERE: Readers may be interested to know that Prof Schapira is also involved with another clinical trial for GBA-associated Parkinson’s disease. The work is being conducted in collaboration with the biotech company Sanofi Genzyme, and involves a phase II trial, called MOVE-PD, which is testing the efficacy, and safety of a drug called GZ/SAR402671 (Click here to read more about this clinical trial). GZ/SAR402671 is a glucosylceramide synthase inhibitor, which will hopefully reduce the production and consequent accumulation of glycosphingolipids in people with a mutation in the GBA gene. This approach is trying to reduce the amount of protein that can not be broken down by the faulty glucocerebrosidase enzyme. The MOVE-PD study will enroll more than 200 patients worldwide (Click here and here to read more on this).

The current Phase 1 trial at the Royal Free Hospital will be primarily testing the safety of Ambroxol in GBA-associated Parkinson’s disease. The researchers will, however, be looking to see if Ambroxol can increase levels of glucocerebrosidase and also assess whether this has any beneficial effects on the Parkinson’s features.

So what does it all mean?

There is a major effort from many of the Parkinson’s disease related charitable groups to clinically test available medications for their ability to slow this condition. Big drug companies are not interested in this ‘re-purposing effort’ as many of these drugs are no longer patent protected and thus providing limited profit opportunities for them. This is one of the unfortunate realities of the pharmaceutical industry business model.

One of the most interesting drugs being tested in this re-purposing effort is the respiratory disease-associated treatment, Ambroxol. Recently new research has been published that indicates Ambroxol is able to enter the brain and have an impact by increasing the level of protein disposal activity.

A clinical trial testing Ambroxol in Parkinson’s disease is underway and we will be watching for the results when they are released (most likely late 2019/early 2020, though preliminary results may be released earlier).

This trial is worth watching.

Stay tuned.

EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. Amboxol is a commercially available medication, but it is not without side effects (for more on this, see this website). We urge caution and professional consultation before altering a treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.

The banner for today’s post was sourced from Pharmacybook

Editorial: Putting 200 years into context

April 12, 2017April 12, 2017 ~ Simon ~ 4 Comments

200

Here at the SoPD we understand and are deeply sympathetic to the frustration felt by the Parkinson’s community regarding the idea of ‘200 years and still no cure’.

As research scientists, we are in the trench everyday – fighting the good fight – trying to find ways of alleviating this terrible condition. And some of us are also in the clinics, interacting with sufferers and their families, listening to their stories and trying to help. While we do not deal directly with the day-to-day trials of living with Parkinson’s disease, we are keenly aware of many of the issues and are fully invested in trying to correct this condition.

972px-Paralysis_agitans_(1907,_after_St._Leger)

Source: Wikipedia

We do feel, however, that it is important to put some context into that ‘200 years’ time point that we are observing this week. It is too easy for people to think “wow, 200 years and still no cure?”

In our previous post – made in collaboration with Prof Frank Church of the Journey with Parkinson’s blog – we listed the major historical milestones and discoveries made in the Parkinson’s disease field during the last 200 years.

The most striking feature of that time line, however, is how just little actually happened during the first 100 years.

In fact for most of that period, Parkinson’s disease wasn’t even called ‘Parkinson’s disease’.

Of the 48 events that we covered on that time line, 37 of them have occurred in the last 50 years (26 since 2000).

Taking this line of thought one step further, 2017 is also the 20 year anniversary of the discovery of alpha synuclein‘s association with Parkinson’s disease. And what a remarkable 20 years that has been. In 1997, a group of researcher at the National institute of Health led by Robert Nussbaum reported the first genetic mutation in the alpha synuclein gene that infers vulnerability to Parkinson’s disease.

Since then, we have:

identified multiple additional mutations within that same gene that increase the risk of developing Parkinson’s disease.
determined which forms of alpha synuclein are toxic.
identified alpha synuclein as an important component of Lewy bodies – the dense clusters of protein found in the Parkinsonian brain.
discovered numerous methods by which alpha synuclein can be passed between cells – potentially aiding in the spread of Parkinson’s disease.
developed and validated models of Parkinson’s disease based on manipulations of alpha synuclein (including numerous genetically engineered mice, viral over-expression models, etc).
identified alpha synuclein in the lining of the gut of people with Parkinson’s disease and this has aided us in developing new theories as to how the condition may start.
set up and run numerous clinical trials targeting alpha synuclein (and we eagerly await the results of those trials).
published over 6200 scientific papers (don’t believe me? Click here) – that’s over 300 publications per year!

Alpha synuclein protein. Source: Wikipedia

And the truly amazing part? All of these particular achievements are only dealing with just the one gene: alpha synuclein.

Since the identification of the alpha synuclein mutations, we have subsequently discovered genetic mutations in over 20 other genes that increase the risk of developing Parkinson’s disease. And we have conducted the same activities/experiments for most of those genes as we have for alpha synuclein.

For example, in 2004 we discovered that people with genetic mutations in a gene called glucocerebrosidase (or GBA) had an increased risk of developing Parkinson’s disease. In 2016, just 12 years after that discovery we have started a clinical trial designed specifically for those people (Click here for more on this).

wwwnew2_0

Source: Parkinson’s UK

We here at the SoPD are fully supportive of campaigns like #WeWontWait, and this post was not written (nor meant to be taken) as an excuse response to the ‘200 years and no cure’ frustration. I can understand how it may be read that way, but I did not know how else to write it. And I thought it needed to be written.

The point of this entire post is that those 200 years need to be put into context.

And while all of these words aren’t going to make life easier for someone living with Parkinson’s to deal with their situation, in addition to raising awareness this week I think it is important for the Parkinson’s community to also understand just how far we have come, and how fast we are currently progressing.

The question can be asked: will this be the last major anniversary we acknowledge with regards to Parkinson’s disease?

I sincerely think that there is cause to hope that it is.

Let me finish with a personal note:

I have a good friend – let’s call him Matt.

As a young boy, Matt remembers his grandfather having Parkinson’s disease. He remembers growing up watching the trials and tribulations that the old man went through with the condition. There were basically no treatment options when Matt’s grandfather was diagnosed and little in the way of support for the family. His grandfather’s body simply froze up as the disease progressed. L-dopa probably only became available to Matt’s grandfather during the latter stages of the disease.

Four years ago Matt’s father was diagnosed with Parkinson’s disease.

Thanks to scientific advances, however, Matt’s dad now has a wide range of treatment options on the medication side of things. The disease can be managed so that he can still play his golf and enjoy his retirement – in a way that his own father never could. He also has numerous surgical options once those medications lose their effectiveness (eg. deep brain stimulation, Pallidotomy, etc). The chances are very likely that Matt’s father will pass on by natural causes before he requires many of those additional options.

This is the progress that we have made.

But there is still a lot of work to be done of course.

During a lunch shortly after his father’s diagnosis, Matt looked squarely across the table at me. Me, the Parkinson’s researcher. All of the usual jovial nature was missing from his face and he simply muttered the words ‘hurry up’.

Whether he was speaking for his father, himself or his own young kids, I understood where his words were coming from and the sentiment.

And, as this post and the previous post point out, we are hurrying up.

The banner for today’s post was sourced from BMO

Milestones in Parkinson’s disease research and discovery

April 11, 2017April 12, 2017 ~ Simon ~ 4 Comments

Self-Reflected-in-violets

For today’s post, we have teamed up with Prof Frank Church from the Journey with Parkinson’s blog to bring readers an ‘Introduction to the historical timeline on Parkinson’s disease’.

The idea for this project started as a conversation between Frank and his partner Barbara during a recent weekend at the beach in North Carolina.

Frank said: “Wouldn’t it be cool to publish a Parkinson’s historical timeline for Parkinson’s awareness month?”

However, to complete this project Frank felt it necessary to bring in some extra help in the form of a Parkinson’s expert.

And when everyone else said they were too busy, Frank contacted us.

Truly flattered, we immediately said yes. And the rest is history.

We are happy to present the milestones in Parkinson’s disease research and discover, though we do apologise to the clinicians, scientists, health-care specialists, and their projects that were not cited here but we limited the timeline to ~50 notations.

Below there are six panels outlining different stages of the history of Parkinson’s disease, and under each of them we have briefly described each of the events in the panel.

We hope you like it.

1817-1919- Milestones in Parkinson’s Disease Research and Discovery (Part 1a: Historical):

First description of Parkinson’s disease

In 1811, Mr James Parkinson of no. 1 Hoxton Square (London) published a 66 page booklet called an ‘An Essay on the Shaking Palsy’. At the date of printing, it sold for 3 shillings (approx. £9 or US$12). The booklet was the first complete description of a condition that James called ‘Paralysis agitans’ or shaking palsy. In his booklet, he discusses the history of tremor and distinguishes this new condition from other diseases. He then describes three of his own patients and three people who he saw in the street.

The naming of Parkinson’s disease

Widely considered the ‘Father of modern neurology’, the importance of Jean-Martin Charcot’s contribution to modern medicine is rarely in doubt. From Sigmund Freud to William James (one of the founding fathers of Psychology), Charcot taught many of the great names in the early field of neurology. Between 1868 and 1881, Charcot focused much of his attention on the ‘paralysis agitans’. Charcot rejected the label ‘Paralysis agitans’, however, suggesting that it was misleading in that patients were not markedly weak and do not necessarily have tremor. Rather than Paralysis Agitans, Charcot suggested that Maladie de Parkinson (or Parkinson’s disease) would be a more appropriate name, bestowing credit to the man who first described the condition. And thus 70 years after passing away, James Parkinson was immortalized with the disease named after him.

The further clinical characterisation of Parkinson’s disease

British neurologist Sir William Gowers published a two-volume text called the Manual of Diseases of the Nervous System (1886, 1888). In this book he described his personal experience with 80 people with Parkinson’s disease in the 1880s. He also identified the subtle male predominance of the disorder and provided illustrations of the characteristic posture. In his treatment of Parkinson’s tremor, Gower used hyoscyamine, hemlock, and hemp (cannabis) as effective agents for temporary tremor abatement.

The discovery of the chemical dopamine

In the Parkinsonian brain there is a severe reduction in the chemical dopamine. This chemical was first synthesised in 1910 by George Barger and James Ewens at the Wellcome labs in London, England.

The discovery of Lewy bodies

One of the cardinal features of Parkinson’s disease in the brain is the presence of Lewy bodies – circular clusters of protein. In 1912, German neurologist Friedrich Lewy, just two years out of medical school and still in his first year as Director of the Neuropsychiatric Laboratory at the University of Breslau (now Wroclaw, Poland) Medical School discovered these ‘spherical inclusions’ in the brains of a people who had died with Parkinson’s disease.

The importance of the substantia nigra in Parkinson’s disease

The first brain structure to be associated with Parkinson’s disease was the substantia nigra. This region lies in an area called the midbrain and contains the majority of the dopamine neurons in the human brain. It was in 1919 that a Russian graduate student working in Paris, named Konstantin Tretiakoff, first demonstrated that the substantia nigra was associated with Parkinson’s disease. Tretiakoff also noticed circular clusters in the brains he examined and named them ‘corps de Lewy’ (or Lewy bodies) after the German neurologist Friedrich Lewy who first discovered them.

1953-1968- Milestones in Parkinson’s Disease Research and Discovery (Part 1b: Historical):

The first complete pathologic analysis of the Parkinsonian brain

The most complete pathologic analysis of Parkinson’s disease with a description of the main sites of damage was performed in 1953 by Joseph Godwin Greenfield and Frances Bosanquet.

The discovery of a functional role for dopamine in the brain

Until the late 1950s, the chemical dopamine was widely considered an intermediate in the production of another chemical called norepinephrine. That is to say, it had no function and was simply an ingredient in the recipe for norepinephrine. Then in 1958, Swedish scientist Arvid Carlsson discovered that dopamine acts as a neurotransmitter – a discovery that won Carlsson the 2000 Nobel prize for Physiology or Medicine.

The founding of the Parkinson’s Disease Foundation

In 1957, a nonprofit organisation called the Parkinson’s Disease Foundation was founded by William Black. It was committed to finding a cure for Parkinson’s Disease. Since its founding in 1957, PDF has funded more than $115 million worth of scientific research in Parkinson’s disease.

The discovery of the loss of dopamine in the brain of people with Parkinson’s disease

In 1960, Herbert Ehringer and Oleh Hornykiewicz demonstrated that the chemical dopamine was severely reduced in brains of people who had died with Parkinson’s disease.

The first clinical trials of Levodopa

Knowing that dopamine can not enter the brain and armed with the knowledge that the chemical L-dopa was the natural ingredient in the production of dopamine, Oleh Hornykiewicz & Walther Birkmayer began injecting people with Parkinson’s disease with L-dopa in 1961. The short term response to the drug was dramatic: “Bed-ridden patients who were unable to sit up, patients who could not stand up when seated, and patients who when standing could not start walking performed all these activities with ease after L-dopa. They walked around with normal associated movements and they could even run and jump.” (Birkmayer and Hornykiewicz 1961).

The first internationally-used rating system for Parkinson’s disease

In 1967, Melvin Yahr and Margaret Hoehn published a rating system for Parkinson’s disease in the journal Neurology. It involves 5 stages, ranging from unilateral symptoms but no functional disability (stage 1) to confinement to wheel chair (stage 5). Since then, a modified Hoehn and Yahr scale has been proposed with the addition of stages 1.5 and 2.5 in order to help better describe the intermediate periods of the disease.

Perfecting the use of L-dopa as a treatment for Parkinson’s disease

In 1968, Greek-American scientist George Cotzias reported dramatic effects on people with Parkinson’s disease using oral L-dopa. The results were published in the New England Journal of Medicine. and L-dopa becomes a therapeutic reality with the Food and Drug Administration (FDA) approving the drug for use in Parkinson’s disease in 1970. Cotzias and his colleagues were also the first to describe L-dopa–induced dyskinesias.

1972-1997- Milestones in Parkinson’s Disease Research and Discovery (Part 1c: Historical):

Levodopa + AADC inhibitors (carbidopa or benserazide)

When given alone levodopa is broken down to dopamine in the bloodstream, which leads to some detrimental side effects. By including an aromatic amino acid decarboxylase (AADC) inhibitor with levodopa allows the levodopa to get to the blood-brain barrier in greater amounts for better utilisation by the neurons. In the U.S., the AADC inhibitor of choice is carbidopa and in other countries it’s benserazide.

The discovery of dopamine agonists

Dopamine agonists are ‘mimics’ of dopamine that pass through the blood brain barrier to interact with target dopamine receptors. Since the mid-1970’s, dopamine agonists are often the first medication given most people to treat their Parkinson’s; furthermore, they can be used in conjunction with levodopa/carbidopa. The most commonly prescribed dopamine agonists in the U.S. are Ropinirole (Requip®), Pramipexole (Mirapex®), and Rotigotine (Neupro® patch). There are some challenging side effects of dopamine agonists including compulsive behaviour (e.g., gambling and hypersexuality), orthostatic hypotension, and hallucination.

The clinical use of MAO-B inhibitors

In the late-1970’s, monoamine oxidase-B (MAO-B) inhibitors were created to block an enzyme in the brain that breaks down levodopa. MAO-B inhibitors have a modest effect in suppressing the symptoms of Parkinson’s. Thus, one of the functions of MAO-B inhibitors is to prolong the half-life of levodopa to facilitate its use in the brain. Very recently in clinical trials, it’s been shown that MAO-B inhibitors have some neuroprotective effect when used long-term. The most widely used MAO-B inhibitors in the U.S. include Rasagiline (Azilect) and Selegiline (Eldepryl and Zelpar); MAO-B inhibitors may reduce “off” time and extend “on” time of levodopa.

Fetal Cell transplantation

After successful preclinical experiments in rodents, a team of researchers in Sweden, led by Anders Bjorklund and Olle Lindvall, began the first clinical trials of fetal cell transplantation for Parkinson’s disease. These studies involved taking embryonic dopamine cells and injecting them into the brains of people with Parkinson’s disease. The cells then matured and replaced the cells that had been lost during the progression of the disease.

The discovery of MPTP

In July of 1982, Dr. J. William Langston of the Santa Clara Valley Medical Center in San Jose (California) was confronted with a group of heroin addicts who were completely immobile. A quick investigation demonstrated that the ‘frozen addicts’ had injected themselves with a synthetic heroin that had not been prepared correctly. The heroin contained a chemical called MPTP, which when injected into the body rapidly kills dopamine cells. This discovery provided the research community with a new tool for modelling Parkinson’s disease.

1997-2006- Milestones in Parkinson’s Disease Research and Discovery (Part 1d: Historical):

Alpha synuclein becomes the first gene associated with familial cases of Parkinson’s disease and its protein is found in Lewy bodies

In 1997, a group of researchers at the National institute of Health led by Robert Nussbaum reported the first genetic aberration linked to Parkinson’s disease. They had analysed DNA from a large Italian family and some Greek familial cases of Parkinson’s disease, and they

The gene Parkin becomes the first gene associated with juvenile Parkinson’s disease

The gene Parkin provides the instructions for producing a protein that is involved with removing rubbish from within a cell. In 1998, a group of Japanese scientists identified mutations in this gene that resulted in affected individuals being vulnerable to developing a very young onset (juvenile) version of Parkinson’s disease.

The first use of PET scan brain imaging for Parkinson’s disease

Using the injection of a small amount of radioactive material (known as a tracer), the level of dopamine present in an area of the brain called the striatum could be determined in a live human being. Given that amount of dopamine in the striatum decreases over time in Parkinson’s disease, this method of brain scanning represented a useful diagnostic aid and method of potentially tracking the condition.

The launch of Michael J Fox Foundation

In 1991, actor Michael J Fox was diagnosed with young-onset Parkinson’s disease at 29 years of age. Upon disclosing his condition in 1998, he committed himself to the campaign for increased Parkinson’s research. Founded on the 31^st October, 2000, the Michael J Fox Foundation has funded more than $700 million in Parkinson’s disease research, representing one of the largest non-governmental sources of funding for Parkinson’s disease.

The Braak Staging of Parkinson’s pathology

In 2003, German neuroanatomist Heiko Braak and colleagues presented a new theory of how Parkinson’s disease spreads based on the postmortem analysis of hundreds of brains from people who had died with Parkinson’s disease. Braak proposed a 6 stage theory, involving the disease spreading from the brain stem (at the top of the spinal cord) up into the brain and finally into the cortex.

The gene DJ1 is linked to early onset PD

DJ1 (also known as PARK7) is a protein that inhibits the aggregation of Parkinson’s disease-associated protein alpha synuclein. In 2003, researchers discovered mutations in the DJ1 gene that made people vulnerable to a early-onset form of Parkinson’s disease.

The first GDNF clinical trial indicates neuroprotection in people with Parkinson’s disease

A small open-label clinical study involving the direct delivery of the chemical Glial cell-derived neurotrophic factor (GDNF) into the brains of people with Parkinson’s disease indicated that neuroprotection. The subjects involved in the study exhibited positive responses to the treatment and postmortem analysis of one subjects brain indicated improvements in the brain.

The genes Pink1 and LRRK2 are associated with early onset PD

Early onset Parkinson’s is defined by age of onset between 20 and 40 years of age, and it accounts for <10% of all patients with Parkinson’s. Genetic studies are finding a causal association for Parkinson’s with five genes: alpha synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1 (PARK7), and Leucine-rich repeat kinase 2 (LRRK2). However it happens, and at whatever age it occurs, there is no doubt that genetics and environment combine together to contribute to the development of Parkinson’s.

The discovery of induced pluripotent stem (IPS) cells

In 2006, Japanese researchers demonstrated that it was possible to take skin cells and genetically reverse engineer them into a more primitive state – similar to that of a stem cell. This amazing achievement involved a fully mature cell being taken back to a more immature state, allowing it to be subsequently differentiated into any type of cell. This research resulted in the discoverer, Shinya Yamanaka being awarded the 2012 Nobel prize for Physiology or Medicine.

2007-2016- Milestones in Parkinson’s Disease Research and Discovery (Part 1e: Historical):

The introduction of the MDS-UPDRS revised rating scale

The Movement Disorder Society (MDS) unified Parkinson’s disease rating scale (UPDRS) was introduced in 2007 to address two limitations of the previous scaling system, namely a lack of consistency among subscales and the low emphasis on the non-motor features. It is now the most commonly used scale in the clinical study of Parkinson’s disease.

The discovery of Lewy bodies in transplanted dopamine cells

Postmortem analysis of the brains of people with Parkinson’s disease who had fetal cell transplantation surgery in the 1980-1990s demonstrated that Lewy bodies are present in the transplanted dopamine cells. This discovery (made by three independent research groups) suggests that Parkinson’s disease can spread from unhealthy cells to healthy cells. This finding indicates a ‘prion-like’ spread of the condition.

SNCA, MAPT and LRRK2 are risk genes for idiopathic Parkinson’s disease

Our understanding of the genetics of Parkinson’s is rapidly expanding. There is recent evidence of multiple genes linked to an increase the risk of idiopathic Parkinson’s. Interestingly, microtubule-associated protein tau (MAPT) is involved in microtubule assembly and stabilization, and it can complex with alpha synuclein (SNCA). Future therapies are focusing on the reduction and clearance of alpha synuclein and inhibition of Lrrk2 kinase activity.

IPS derived dopamine neurons from people with Parkinson’s disease

The ability to generate dopamine cells from skin cells derived from a person with Parkinson’s disease represents not only a tremendous research tool, but also opens the door to more personalized treatments of suffers. Induced pluripotent stem (IPS) cells have opened new doors for researchers and now that we can generate dopamine cells from people with Parkinson’s disease exciting opportunities are suddenly possible.

Neuroprotective effect of exercise in rodent Parkinson’s disease models

Exercise has been shown to be both neuroprotective and neurorestorative in animal models of Parkinson’s. Exercise promotes an anti-inflammatory microenvironment in the mouse/rat brain (this is but one example of the physiological influence of exercise in the brain), which helps to reduce dopaminergic cell death. Taking note of these extensive and convincing model system results, many human studies studying exercise in Parkinson’s are now also finding positive benefits from strenuous and regular exercise to better manage the complications of Parkinson’s.

Transeuro cell transplantation trial begins

In 2010, a European research consortium began a clinical study with the principal objective of developing an efficient and safe treatment methodology fetal cell transplantation in people with Parkinson’s disease. The trial is ongoing and the subjects will be followed up long term to determine if the transplantation can slow or reverse the features of Parkinson’s disease.

Successful preclinical testing of dopamine neurons from embryonic stem cells

Scientists in Sweden and New York have successfully generated dopamine neurons from human embryonic stem cells that can be successfully transplanted into animal models of Parkinson’s disease. Not only do the cells survive, but they also correct the motor deficits that the animals exhibit. Efforts are now being made to begin clinical trials in 2018.

Microbiome of the gut influences Parkinson’s disease

Several research groups have found the Parkinson’s disease-associated protein alpha synuclein in the lining of the gut, suggesting that the intestinal system may be one of the starting points for Parkinson’s disease. In 2016, researchers found that the bacteria in the stomachs of people with Parkinson’s disease is different to normal healthy individuals. In addition, experiments in mice indicated that the bacteria in the gut can influence the healthy of the brain, providing further evidence supporting a role for the gut in the development of Parkinson’s disease.

2016-2017- Milestones in Parkinson’s Disease Research and Discovery (Part 2: Clinical trials either recently completed or in progress)

Safety, Tolerability and Efficacy Assessment of Dynacirc (Isradipine) for PD (STEADY-PD) III trial

Isradipine is a calcium-channel blocker approved for treating high blood pressure; however, Isradipine is not approved for treating Parkinson’s. In animal models, Isradipine has been shown to slow the progression of PD by protecting dopaminergic neurons. This study is enrolling newly diagnosed PD patients not yet in need of symptomatic therapy. Participants will be randomly assigned Isradipine or given a placebo.

Treatment of Parkinson’s Psychosis with Nuplazid

Approximately 50% of the people with Parkinson’s develop psychotic tendencies. Treatment of their psychosis can be relatively difficult. However, a new drug named Nuplazid was recently approved by the FDA specifically designed to treat Parkinson’s psychosis.

Opicapone (COMT Inhibitor) as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations

Catechol-O-methyl transferase (COMT) inhibitors prolong the effect of levodopa by blocking its metabolism. COMT inhibitors are used primarily to help with the problem of the ‘wearing-off’ phenomenon associated with levodopa. Opicapone is a novel, once-daily, potent third-generation COMT inhibitor. It appears to be safer than existing COMT drugs. If approved by the FDA, Opicapone is planned for use in patients with Parkinson’s taking with levodopa who experience wearing-off issues.

Nilotinib (Tasigna® by Novartis) indicates positive results in phase I trial.

Nilotinib is a drug used in the treatment of leukemia. In 2015, it demonstrated beneficial effects in a small phase I clinical trial of Parkinson’s disease. Researchers believe that the drug activates the disposal system of cells, thereby helping to make cells healthier. A phase II trial of this drug to determine how effective it is in Parkinson’s disease is now underway.

ISCO cell transplantation trial begins

International Stem Cell Corporation is currently conducting a phase I clinical cell transplantation trial at a hospital in Melbourne, Australia. The company is transplanting human parthenogenetic stem cells-derived neural stem cells into the brains of people with Parkinson’s disease. The participants will be assessed over 12 months to determine whether the cells are safe for use in humans.

Neuropore’s alpha-synuclein stabilizer (NPT200-11) passes phase I trial

Neuropore Therapies is a biotech company testing a compound (NPT200-11) that inhibits and stablises the activity of the Parkinson’s disease-associated protein alpha synuclein. This alpha-synuclein inhibitor has been shown to be safe and well tolerated in humans in a phase I clinical trial and the company is now developing a phase II trial.

mGluR4 PAM (PXT002331) well tolerated in phase I trial

Prexton Therapeutics recently announced positive phase I clinical trial results for their lead drug, PXT002331, which is the first drug of its kind to be tested in Parkinson’s disease. PXT002331 is a mGluR4 PAM – this is a class of drug that reduces the level of inhibition in the brain. In Parkinson’s disease there is an increase in inhibition in the brain, resulting in difficulties with initiating movements. Phase II clinical trials to determine efficacy are now underway.

Initial results of Bristol GDNF trial indicate no effect

Following remarkable results in a small phase I clinical study, the recent history of the neuroprotective chemical GDNF has been less than stellar. A subsequent phase II trial demonstrated no difference between GDNF and a placebo control, and now a second phase II trial in the UK city of Bristol has reported initial results also indicating no effect. Given the initial excitement that surrounded GDNF, this result has been difficult to digest. Additional drugs that behave in a similar fashion to GDNF are now being tested in the clinic.

Immunotherapies proves safe in phase I trials (AFFiRis & Prothena)

Immunotherapy is a treatment approach which strengthens the body’s own immune system. Several companies (particularly ‘AFFiRis’ in Austria and ‘Prothena’ in the USA) are now conducting clinical trials using treatments that encourage the immune system to target the Parkinson’s disease-associated protein alpha synuclein. Both companies have reported positive phase I results indicating the treatments are well tolerable in humans, and phase II trials are now underway.

Living Cell Technologies Limited continue Phase II trial of NTCELL

A New Zealand company called Living Cell Technologies Limited have been given permission to continue their phase II clincial trial of their product NTCELL, which is a tiny capsule that contains cells which release supportive nutrients when implanted in the brain. The implanted participants will be blindly assessed for 26 weeks, and if the study is successful, the company will “apply for provisional consent to treat paying patients in New Zealand…in 2017”.

MAO-B inhibitors shown to be neuroprotective.

MAO-B inhibitors block/slow the break down of the chemical dopamine. Their use in Parkinson’s disease allows for more dopamine to be present in the brain. Recently, several longitudinal studies have indicated that this class of drugs may also be having a neuroprotective effect.

Inhalable form of L-dopa

Many people with Parkinson’s disease have issues with swallowing. This makes taking their medication in pill form problematic. Luckily, a new inhalable form of L-dopa will shortly become available following recent positive Phase III clinical trial results, which demonstrated a statistically significant improvements in motor function for people with Parkinson’s disease during OFF periods.

Exenatide trial results expected

Exenatide is a drug that is used in the treatment of diabetes. It has also demonstrated beneficial effects in preclinical models of Parkinson’s disease, as well as an open-label clinical study over a 14 month period. Interestingly, in a two year follow-up study of that clinical trial – conducted 12 months after the patients stopped receiving Exenatide – the researchers found that patients previously exposed to Exenatide demonstrated significant improvements compared to how they were at the start of the study. There is currently a placebo-controlled, double blind phase II clinical trial being conducted and the results should be reported before the end of 2017.

A personal reflection

As I suggested at the start of this post, this endeavour was entirely Frank’s idea – full credit belongs with him. I was more than happy to help him out with it though as I thought it was a very worthy project. During this 200 year anniversary, I believe it is very important to acknowledge just how far we have come in our understanding of Parkinson’s disease since James first put pen to paper and described the six cases he had seen in London.

And Frank’s idea perfectly captures this.

The banner for today’s post was sourced from Greg Dunn (we are big fans!)

ADHD and Parkinson’s disease

March 23, 2017March 30, 2017 ~ Simon ~ 26 Comments

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The chemical dopamine plays a critical role in Parkinson’s disease.

It is also involved with the condition Attention deficit hyperactivity disorder, and recently researchers have been looking at whether there are any links between the two.

In today’s post we will look at what Attention deficit hyperactivity disorder is, how it relates to Parkinson’s disease, and what new research means for the community.

Source: Huffington Post

We really have little idea about how Parkinson’s disease actually develops.

It could be kicked off by a virus or environmental factors or genetics…or perhaps a combination of these. We really don’t know, and it could vary from person to person.

There is a lot of speculation, however, as to what additional conditions could make one susceptible to Parkinson’s disease, even those conditions with early developmental onsets, such as autism (which we have previously written about – click here to see that post).

Recently researchers in Germany have asked if there is any connections between Parkinson’s and ADHD?

What is ADHD?

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition that begins in childhood and persists into adulthood in 60% of affected individuals.

It is classically characterised in the media by hyperactive children who struggle to concentrate and stay focused on what they are doing. They are often treated with drugs such as Methylphenidate (also known as ritalin). Methylphenidate acts by blocking a protein called the dopamine transporter, which is involved with reabsorbing the chemical dopamine back into the cell after it has performed it’s function.

1280px-Ritalin

Ritalin. Source: Wikipedia

So are there any connections between ADHD and Parkinson’s disease?

This is an interesting question.

While there have been no reported findings of increased (or decreased) frequency of Parkinson’s disease in people with ADHD (to our knowledge), there are actually several bits of evidence suggesting a connection between the two conditions, such as abnormalities in the substantia nigra:

substantia

Title: Structural abnormality of the substantia nigra in children with attention-deficit hyperactivity disorder
Authors: Romanos M, Weise D, Schliesser M, Schecklmann M, Löffler J, Warnke A, Gerlach M, Classen J, Mehler-Wex C.
Journal: J Psychiatry Neurosci. 2010 Jan;35(1):55-8.
PMID: 20040247 (This article is OPEN ACCESS if you would like to read it)

The substantia nigra is a structure in the brain where the dopamine neurons reside. In Parkinson’s disease, the dopamine neurons of the substantia nigra start to degenerate – 50% are lost by the time a person is diagnosed with the condition.

In this study, the researchers used a technique called echogenicity to examine the substantia nigra of 22 children with ADHD and 22 healthy controls. Echogenicity is the ‘ability to bounce an echo’. This sort of assessment measures the return of an ultrasound signal that is aimed at a structure.

The researchers found that the ADHD subjects had a larger substantia nigra area than the healthy controls – which apparently indicates dopamine dysfunction. This finding is similar to results that have been observed in Parkinson’s disease (Click here to read more regarding that study).

Another connection between the two conditions was recent research has shown that genetic variations in the PARK2 gene (also known as Parkin) contribute to the genetic susceptibility to ADHD.

Parkin title

Title: Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.
Authors: Jarick I, Volckmar AL, Pütter C, Pechlivanis S, Nguyen TT, Dauvermann MR, Beck S, Albayrak Ö, Scherag S, Gilsbach S, Cichon S, Hoffmann P, Degenhardt F, Nöthen MM, Schreiber S, Wichmann HE, Jöckel KH, Heinrich J, Tiesler CM, Faraone SV, Walitza S, Sinzig J, Freitag C, Meyer J, Herpertz-Dahlmann B, Lehmkuhl G, Renner TJ, Warnke A, Romanos M, Lesch KP, Reif A, Schimmelmann BG, Hebebrand J, Scherag A, Hinney A.
Journal: Mol Psychiatry. 2014 Jan;19(1):115-21.
PMID: 23164820 (This article is OPEN ACCESS if you would like to read it)

There are about 20 genes that have been associated with Parkinson’s disease, and they are referred to as the PARK genes. Approximately 10-20% of people with Parkinson’s disease have a genetic variation in one or more of these PARK genes (we have discussed these before – click here to read that post). PARK2 is a gene called Parkin. Mutations in Parkin can result in an early-onset form of Parkinson’s disease. The Parkin gene produces a protein which plays an important role in removing old or sick mitochondria (we discussed this in our previous post – click here to read that post).

In this report, the researchers conducted a genetic sequencing study on 489 young subjects with ADHD (average age 11 years old) and 1285 control individuals. They replicated the study with a similar sized population of people affected by ADHD and control subjects, and in both studies they found that certain deletions and replications in the Parkin gene influences susceptibility to ADHD – two of the genetic variations were found in 335 of the ADHD cases and none in 2026 healthy controls (from both sets of studies).

So there are are some interesting possible connections between ADHD and Parkinson’s disease.

And what has the recent research from the German scientists found?

In this study, the researchers have looked at additional genetic variations that have been suggested to infer susceptibility to ADHD.

adhd

Title: No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease in nine ADHD candidate SNPs
Authors: Geissler JM; International Parkinson Disease Genomics Consortium members., Romanos M, Gerlach M, Berg D, Schulte C.
Journal: Atten Defic Hyperact Disord. 2017 Feb 7. doi: 10.1007/s12402-017-0219-8. [Epub ahead of print]
PMID: 28176268

The researchers analysed nine genetic variations in seven genes:

one variant in the gene synaptosomal-associated protein, 25kDa1 (SNAP25)
one variant in the gene dopamine transporter (DAT; also known as SLC6A3)
one variant in the gene dopamine receptor D4 (DRD4)
one variant in the gene serotonin receptor 1B (HTR1B)
three mutations in cadherin 13 (CDH13)
one mutation located within the gene tryptophan hydroxylase 2 (TPH2)
one mutation located within the gene noradrenaline transporter (SLC6A2)

These genetic variations were assessed in 5333 cases of Parkinson’s disease and 12,019 healthy controls. The researchers found no association between any of the genetic variants and Parkinson’s disease. This finding lead the investigators to conclude that these genetic alterations associated with ADHD do not play a substantial role in increasing the risk of developing Parkinson’s disease.

Have ADHD medications ever been tested in Parkinson’s disease?

Yes.

Given the association of both ADHD and Parkinson’s disease with altered dopamine processing in the brain, a clinical trial of ritalin in Parkinson’s disease was set up and run in 2006 (Click here to read more about that trial). The results of the trial were published in 2007:

Ritalin title

Title: Effects of methylphenidate on response to oral levodopa: a double-blind clinical trial.
Authors: Nutt JG, Carter JH, Carlson NE.
Journal: Arch Neurol. 2007 Mar;64(3):319-23.
PMID: 17353373 (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers recruited 12 people with Parkinson’s disease and examined their response to 0.4 mg/kg of ritalin – given 3 times per day – in conjunction with their normal anti-Parkinsonian medication (L-dopa). They then tested the subjects with either ritalin or a placebo control and failed to find any clinically significant augmentation of L-dopa treatment from the co-administration of ritalin.

What does it all mean?

So summing up: both Attention deficit hyperactivity disorder (ADHD) and Parkinson’s disease are associated with changes in the processing of the brain chemical dopamine. There are loose connections between the two conditions, but nothing definitive.

It will be interesting to follow up some of the individuals affected by ADHD, to determine if they ultimately go on to develop Parkinson’s (particularly those with Parkin mutations/genetic variants). But until then, the connection between these two conditions is speculative at best.

The banner for today’s post was sourced from Youtube

Resveratrol: From the folks who brought you Nilotinib

March 16, 2017 ~ Simon ~ 11 Comments

vc_spotlightsonoma_breaker_winegrapes_stock_rf_525141953_1280x640

Recently the results of a small clinical study looking at Resveratrol in Alzheimer’s disease were published. Resveratrol has long been touted as a miracle ingredient in red wine, and has shown potential in animal models of Parkinson’s disease, but it has never been clinically tested.

Is it time for a clinical trial?

In today’s post we will review the new clinical results and discuss what they could mean for Parkinson’s disease.

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From chemical to wine – Resveratrol. Source: Youtube

In 2006, there was a research article published in the prestigious journal Nature about a chemical called resveratrol that improved the health and survival of mice on a high-calorie diet (Click here for the press release).

Wine2
Title: Resveratrol improves health and survival of mice on a high-calorie diet.
Authors: Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA.
Journal: Nature. 2006 Nov 16;444(7117):337-42.
PMID: 17086191 (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators placed middle-aged (one-year-old) mice on either a standard diet or a high-calorie diet (with 60% of calories coming from fat). The mice were maintained on this diet for the remainder of their lives. Some of the high-calorie diet mice were also placed on resveratrol (20mg/kg per day).

After 6 months of this treatment, the researchers found that resveratrol increased survival of the mice and insulin sensitivity. Resveratrol treatment also improved mitochondria activity and motor performance in the mice. They saw a clear trend towards increased survival and insulin sensitivity.

The report caused a quite a bit of excitement – suddenly there was the possibility that we could eat anything we wanted and this amazing chemical would safe us from any negative consequences.

Grape

Source: Nature

That report was proceeded by numerous studies demonstrating that resveratrol could extend the life-span of various micro-organisms, and it was achieving this by activating a family of genes called sirtuins (specifically Sir1 and Sir2) (Click here, here and here for more on this).

Subsequent to these reports, there have been numerous scientific publications suggesting that resveratrol is capable of all manner of biological miracles.

Wow! So what is resveratrol?

grapes

Do you prefer your wine in pill form? Source: Patagonia

Resveratrol is a chemical that belongs to a group of compounds called polyphenols. They are believed to act like antioxidants. Numerous plants produce polyphenols in response to injury or when the plant is under attack by pathogens (microbial infections).

Fruit are a particularly good source of resveratrol, particularly the skins of grapes, blueberries, raspberries, mulberries and lingonberries. One issue with fruit as a source of resveratrol, however, is that tests in rodents have shown that less than 5% of the oral dose was observed as free resveratrol in blood plasma (Source). This has lead to the extremely popular idea of taking resveratrol in the form of wine, in the hope that it could have higher bioavailability compared to resveratrol in pill form. Red wines have the highest levels of Resveratrol in their skins (particularly Mabec, Petite Sirah, St. Laurent, and pinot noir). This is because red wine is fermented with grape skins longer than is white wine, thus red wine contains more resveratrol.

EDITOR’S NOTE: Sorry to rain on the parade, but it is important to note here that red wine actually contains only small amounts of resveratrol – less than 3-6 mg per bottle of red wine (750ml). Thus, one would need to drink a great deal of red wine per day to get enough resveratrol (the beneficial effects observed in the mouse study described above required 20mg/kg of resveratrol per day. For a person weighting 80kg, this would equate to 1.6g per day or approximately 250 750ml bottles).

We would like to suggest that consuming red wine would NOT be the most efficient way of absorbing resveratrol. And obviously we DO NOT recommend any readers attempt to drink 250 bottles per day (if that is even possible).

The recommended daily dose of resveratrol should not exceed 250 mg per day over the long term (Source). Resveratrol might increase the risk of bleeding in people with bleeding disorders. And we recommend discussing any change in treatment regimes with your doctor before starting.

So what did they find in the Alzheimer’s clinical study?

Well, the report we will look at today is actually a follow-on to published results from a phase 2/safety clinical trial that were reported in 2015:

Title: A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease.
Authors: Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, Brewer JB, Rissman RA, Raman R, Aisen PS; Alzheimer’s Disease Cooperative Study.
Title: Neurology. 2015 Oct 20;85(16):1383-91.
PMID: 26362286 (This article is OPEN ACCESS if you would like to read it)

The researchers behind the study are associated with the Georgetown research group that conducted the initial Nilotinib clinical study in Parkinson’s disease (Click here for our post on this).

The investigators conducted a randomized, placebo-controlled, double-blind, multi-center phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease. The study lasted 52 weeks and involved 119 individuals who were randomly assigned to either placebo or resveratrol 500 mg orally daily treatment.

EDITOR’S NOTE: We appreciate that is daily dose exceeds the recommended daily dose mentioned above, but it is important to remember that the participants involved in this study were being closely monitored by the study investigators.

Brain imaging and samples of cerebrospinal fluid (the liquid within which the brain sits) were collected at the start of the study and after completion of treatment.

The most important result of the study was that resveratrol was safe and well-tolerated. The most common side effect was feeling nausea and diarrhea in approximately 42% of individuals taking resveratrol (curiously 33% of the participants blindly taking the placebo reported the same thing). There was also a weight loss effect between the groups, with the placebo group gaining 0.5kg on average, while the resveratrol treated group lost 1kg on average.

The second important take home message is that resveratrol crossed the blood–brain barrier in humans. The blood brain barrier prevents many compounds from having any effect in the brain, but it does not stop resveratrol.

The investigators initially found no effects of resveratrol treatment in various Alzheimer’s markers in the cerebrospinal fluid. Not did they see any effect in brain scans, cognitive testing, or glucose/insulin metabolism. The authors were cautious about their conclusions based on these results, however, as the study was statistically underpowered (that is to say, there were not enough participants in the various groups) to detect clinical benefits. They recommended a larger study to determine whether resveratrol is actually beneficial.

While exploring the idea of a larger study, the researchers have re-analysed some of the data, and that brings us to the report we want to review today:

moussa

Title: Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease.
Authors: Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, Turner RS.
Journal: J Neuroinflammation. 2017 Jan 3;14(1):1. doi: 10.1186/s12974-016-0779-0.
PMID: 28086917 (This article is OPEN ACCESS if you would like to read it)

In this report, the investigators conducted a retrospective study re-examining the cerebrospinal fluid and blood plasma samples from a subset of subjects involved in the clinical study described above. In this study, they only looked at the subjects who started with very low levels in the cerebrospinal fluid of a protein called Aβ42.

Amyloid beta (or Aβ) is the bad boy/trouble maker of Alzheimer’s disease; considered to be critically involved in the disease. A fragment of this protein (called Aβ42) begin clustering in the brains of people with Alzheimer’s disease and as a result, low levels of Aβ42 in cerebrospinal fluid have been associated with increased risk of Alzheimer’s disease and considered a possible biomarker of the condition (Click here to read more on this).

The resveratrol study investigators collected all of the data from subjects with cerebrospinal fluid levels of Aβ42 less than 600 ng/ml at the start of the study. This selection criteria gave them 19 resveratrol-treated and 19 placebo-treated subjects.

In this subset re-analysis study, resveratrol treatment appears to have slowed the decline in cognitive test scores (the mini-mental status examination), as well as benefiting activities of daily living scores and cerebrospinal fluid levels of Aβ42.

One of the most striking results from this study is the significant decrease observed in the cerebrospinal fluid levels of a protein called Matrix metallopeptidase 9 (or MMP9) after resveratrol treatment. MMP9 is slowly emerged as an important player in several neurodegenerative conditions, including Parkinson’s disease (Click here to read more on this). Thus the decline observed is very interesting.

This re-analysis indicates beneficial effects in some cases of Alzheimer’s as a result of taking resveratrol over 52 weeks. The researchers concluded that the findings of this re-analysis support the idea of a larger follow-up study of resveratrol in people with Alzheimer’s disease.

Ok, but what research has been done on resveratrol in Parkinson’s disease?

Yes, good question.

One of the earliest studies looking at resveratrol in Parkinson’s disease was this one:

Reserv
Title: Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson’s disease in rats.
Authors: Jin F, Wu Q, Lu YF, Gong QH, Shi JS.
Journal: Eur J Pharmacol. 2008 Dec 14;600(1-3):78-82.
PMID: 18940189

In this study, the researchers used a classical rodent model of Parkinson’s disease (using the neurotoxin 6-OHDA). One week after inducing Parkinson’s disease, the investigators gave the animals either a placebo or resveratrol (at doses of 10, 20 or 40 mg/kg). This treatment regime was given daily for 10 weeks and the animals were examined behaviourally during that time.

The researchers found that resveratrol improved motor performance in the treated animals, with them demonstrating significant results as early as 2 weeks after starting treatment. Resveratrol also reduced signs of cell death in the brain. The investigators concluded that resveratrol exerts a neuroprotective effect in this model of Parkinson’s disease.

Similar results have been seen in other rodent models of Parkinson’s disease (Click here and here to read more).

Subsequent studies have also looked at what effect resveratrol could be having on the Parkinson’s disease associated protein alpha synuclein, such as this report:

PD-title

Title: Effect of resveratrol on mitochondrial function: implications in parkin-associated familiarParkinson’s disease.
Authors: Ferretta A, Gaballo A, Tanzarella P, Piccoli C, Capitanio N, Nico B, Annese T, Di Paola M, Dell’aquila C, De Mari M, Ferranini E, Bonifati V, Pacelli C, Cocco T.
Journal: Biochim Biophys Acta. 2014 Jul;1842(7):902-15.
PMID: 24582596 (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators collected skin cells from people with PARK2 associated Parkinson’s disease.

What is PARK2 associated Parkinson’s disease?

PARK2 is a gene called Parkin. Mutations in Parkin can result in an early-onset form of Parkinson’s disease. The Parkin gene produces a protein which plays an important role in removing old or sick mitochondria.

Hang on a second. Remind me again: what are mitochondria?

We have previously written about mitochondria (click here to read that post). Mitochondria are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.

Mitochondria

Mitochondria and their location in the cell. Source: NCBI

You may remember from high school biology class that mitochondria are bean-shaped objects within the cell. They convert energy from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful and highly organised within the cell, being moved around to wherever they are needed.

Another Parkinson’s associated protein, Pink1 (which we have discussed before – click here to read that post), binds to dysfunctional mitochondria and then grabs Parkin protein which signals for the mitochondria to be disposed of. This process is an essential part of the cell’s garbage disposal system.

Park2 mutations associated with early onset Parkinson disease cause the old/sick mitochondria are not disposed of correctly and they simply pile up making the cell sick. The researchers that collected the skin cells from people with PARK2 associated Parkinson’s disease found that resveratrol treatment partially rescued the mitochondrial defects in the cells. The results obtained from these skin cells derived from people with early-onset Parkinson’s disease suggest that resveratrol may have potential clinical application.

Thus it would be interesting (and perhaps time) to design a clinical study to test resveratrol in people with PARK2 associated Parkinson’s disease.

So why don’t we have a clinical trial?

Resveratrol is a chemical that falls into the basket of un-patentable drugs. This means that big drug companies are not interested in testing it in an expensive series of clinical trials because they can not guarantee that they will make any money on their investment.

There was, however, a company set up in 2004 by the researchers behind the original resveratrol Nature journal report (discussed at the top of this post). That company was called “Sirtris Pharmaceuticals”.

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Source: Crunchbase

Sirtris identified compounds that could activate the sirtuins family of genes, and they began testing them. They eventually found a compound called SRT501 which they proposed was more stable and 4 times more potent than resveratrol. The company went public in 2007, and was subsequently bought by the pharmaceutical company GlaxoSmithKline in 2008 for $720 million.

Sirtris_rm

Source: Xconomy

From there, however, the story for SRT501… goes a little off track.

In 2010, GlaxoSmithKline stopped any further development of SRT501, and it is believed that this decision was due to renal problems. Earlier that year the company had suspended a Phase 2 trial of SRT501 in a type of cancer (multiple myeloma) because some participants in the trial developed kidney failure (Click here to read more).

Then in 2013, GlaxoSmithKline shut down Sirtris Pharmaceuticals completely, but indicated that they would be following up on many of Sirtris’s other sirtuins-activating compounds (Click here to read more on this).

Whether any of those compounds are going to be tested on Parkinson’s disease is yet to be determined.

What we do know is that the Michael J Fox foundation funded a study in this area in 2008 (Click here to read more on this), but we are yet to see the results of that research.

We’ll let you know when we hear of anything.

So what does it all mean?

Summing up: Resveratrol is a chemical found in the skin of grapes and berries, which has been shown to display positive properties in models of neurodegeneration. A recent double blind phase II efficacy trial suggests that resveratrol may be having positive benefits in Alzheimer’s disease.

Preclinical research suggests that resveratrol treatment could also have beneficial effects in Parkinson’s disease. It would be interesting to see what effect resveratrol would have on Parkinson’s disease in a clinical study.

Perhaps we should have a chat to the good folks at ‘CliniCrowd‘ who are investigating Mannitol for Parkinson’s disease (Click here to read more about this). Maybe they would be interested in resveratrol for Parkinson’s disease.

ONE LAST EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. SoPD can not be held responsible for actions taken based on the information provided here.

The banner for today’s post was sourced from VisitCalifornia

A yeast model of Parkinson’s disease

March 13, 2017March 13, 2017 ~ Simon ~ 4 Comments

yeast-cell

When I say the word ‘yeast’, you might think of making bread or beer.

One does not automatically think of Parkinson’s disease.

But yeast has actually been incredibly useful in enhancing our understanding of the genetics of Parkinson’s disease, and may well now provide us with novel treatments for the condition. In today’s post we will discuss how yeast research is leading the way for Parkinson’s disease.

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Prof Susan Lindquist. Source: WallStreetJournal

It was with sadness that we heard about the passing of Prof Susan Lindquist in October last year. She was truly a pioneer in the field of molecular biology. In addition to advancing our understanding of gene functioning in degenerative diseases like Parkinson’s disease and Alzheimer’s, she also started a company, Yumanity, which is currently testing new drugs to tackle these conditions. Hopefully her legacy will have enormous impact for the millions of people around the world struggling with these conditions.

And that legacy all started with a bold (some even called it ‘crazy’) idea.

It involved yeast.

What is yeast?

Quite possibly the earliest domesticated species, yeast is a single-celled microorganism, traditionally classified as a member of the fungus kingdom. The evolutionary lineage of yeast dates back hundreds of millions of years old and there are at least 1500 species of yeast (Source: Wikipedia).

cell

The cellular structure of yeast. Source: Biocourseware

More importantly, yeast is one of the most centrally important model organisms used in modern biological research, representing one of the most thoroughly researched organisms in the world.

We know more about the biology of yeast than we do about ourselves!

And this statement is made further evident as researchers use yeast to produce the world’s first synthetic organism (an organism for which the genome has been designed or engineered). By the end of 2017, the Synthetic Yeast 2.0 consortium plans to have produced a new form of yeast in which all 16 chromosomes will have been made in the lab (for more on this, read this STAT article).

Why do scientists like studying yeast?

The main reason is that yeast cells are very similar to human cells, but they grow a lot faster (human cells on average divide a rate of about once every 12 hours, while yeast cells divide every two hours). Yeast is similar to human cells in that it has all of the eukaryote structures, including a nucleus, cytoplasm, and mitochondria (eukaryote meaning a cell with a nucleus).

Yeast has played a fundamental role in many major scientific discoveries since the early 1900s. In 1907, German scientist Edward Buchner won the Nobel Prize in Chemistry for research involving yeast extract and fermentation. Ninety one years later (2006), Roger D. Kornberg won the same prize for his work on DNA transcription using yeast.

Yeast was the first eukaryote to have its genome (DNA) fully sequenced (in 1996). Yeast is literally leading the way in biological research.

So what has this got to do with Parkinson’s disease?

This is where Prof Susan Lindquist comes into the story.

maxresdefault

Source: Youtube

In the early 2000s, she suggested the idea of using yeast to look at neurodegenerative conditions like Parkinson’s disease. It was a wild concept. Talking to the New York Times in 2007, she said “Even people in my laboratory thought we were crazy to try to study neurodegenerative diseases with a yeast cell. It’s not a neuron”.

But they persevered and in 2003 they published this research report in the journal Science:

yeast

Title: Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein.
Authors: Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ.
Journal: Science. 2003; 302(5651):1769-72.
PMID: 14657499

In this study, the researchers conducted a genome-wide screens of mutant genes in yeast to identify genes that enhanced the toxic effects of the mutant huntingtin gene or alpha-synuclein protein. That is to say, they randomly mutated (made un-operational) just one gene per yeast cell, and these yeast cells either had the mutant huntingtin gene (which causes the neurodegenerative condition of Huntington’s disease) or too much alpha synuclein (which causes protein clumping in the yeast cells). Using this approach, they could determine which genes were responsible for increasing the negative effects of the mutant huntington gene or the alpha synuclein protein.

Of the 4850 yeast genes that the researcher mutated (and can we just point out that that is A LOT of work!!!), 52 were identified that exaggerated the affect of the mutant huntingtin gene and 86 increased sensitivity to alpha-synuclein (curiously, only one mutant gene resulted in increased sensitivity to both).

When they looked at the known functions of 86 genes that were increasing the sensitivity to alpha synuclein, the researchers found that most of them were involved in the processes of lipid metabolism (the synthesis and degradation of lipids) and vesicle-mediated transport (this occurs at the tips of neural branches – where alpha synuclein is located). Alpha synuclein is known to be involved with lipid metabolism (Click here and here for more on this). This reenforced the belief with the researchers that yeast could be used to assess disease relevant pathways – this study gave them the ‘proof of concept’.

In addition, the majority of the genes had human ‘orthologs’ (genes in different species that evolved from a common ancestral gene), meaning that the findings of yeast studies could potentially be translated to higher order creatures, like humans. The researchers concluded that they had found cell autonomous genes that are relevant to Parkinson’s disease.

With the publication of this work, people in Prof Lindquist’s lab were probably thinking the idea wasn’t so crazy anymore.

And this first publication led to many more, such as this report which was published in the same journal in 2006:

Linds
Title: Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models.
Authors: Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S.
Journal: Science. 2006 Jul 21;313(5785):324-8.
PMID: 16794039 (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers doubled the amount of alpha synuclein that yeast cells produce and they observed that the cell stopped growing and started to die. They then looked at the earliest cellular events following theover production of alpha synuclein and they noticed that there was a blockage in the endoplasmic reticulum (ER)-to-Golgi vesicular trafficking.

Yes, I know what you are going to ask: What is ER-to-Golgi vesicular trafficking?

The endoplasmic reticulum (or ER) is a network of tubules connected to the nucleus. It is involved in the production of proteins and lipids, which are then transported to the Golgi apparatus which then modifies them, sorts them and and packs them into small bags called vesicles. These vesicles can then be taken to the cell membrane where the proteins are released to do their jobs.

ergolgi

The ER to Golgi pathway. Source: Welkescience

Now the fact that too much alpha synuclein was blocking this pathway was interesting, but the researchers wanted to go further. They conducted another genome-wide screens of genes in yeast to identify genes that could rescue this blockage – BUT this time, instead of mutating genes, the researchers randomly over produced one protein (and there was 3000 of them!!!) in each cell. Because the overproduction of alpha synuclein kills the yeast cells, all the researchers had to do was wait until the end of the experiment and determine which protein was over produced in the surviving cells.

And this led them to a protein called RAB1.

RAB1 is a protein that is critical to the transportation of proteins in cells. The researchers next tested the ability of RAB1 to rescue dopamine cells in Drosophila (flies), Caenorhabditis elegans (microscopic worms), and cell culture models of Parkinson’s disease and they found that it was able to rescue the cells in all three cases. While this result was very interesting, it also provided full validation of the approach that Prof Lindquist and her colleagues were taking using yeast cells to find new therapies for neurodegenerative conditions, like Parkinson’s disease.

But Prof Lindquist and her colleagues didn’t stop there.

Over the next decade numerous research reports were published taking advantage of this approach, including these two reports which appeared back-to-back in the journal Science:

lindq1

Title: Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons.
Authors: Chung CY, Khurana V, Auluck PK, Tardiff DF, Mazzulli JR, Soldner F, Baru V, Lou Y, Freyzon Y, Cho S, Mungenast AE, Muffat J, Mitalipova M, Pluth MD, Jui NT, Schüle B, Lippard SJ, Tsai LH, Krainc D, Buchwald SL, Jaenisch R, Lindquist S.
Journal: Science. 2013 Nov 22;342(6161):983-7.
PMID: 24158904

And:

lindq2

Title: Yeast reveal a “druggable” Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons.
Authors: Tardiff DF, Jui NT, Khurana V, Tambe MA, Thompson ML, Chung CY, Kamadurai HB, Kim HT, Lancaster AK, Caldwell KA, Caldwell GA, Rochet JC, Buchwald SL, Lindquist S.
Journal: Science. 2013 Nov 22;342(6161):979-83.
PMID: 24158909

In these reports, Prof Lindquist and colleagues tested whether some of the proteins that had come up in their various screens could actually have positive benefits in human cells, specifically induced pluripotent stem (iPS) cells (which we have discussed before – click here to read that post). The researchers grew brains cells (neurons and glial cells) from the iPS cells derived from people who suffered from Parkinson’s disease with dementia. These cells exhibited a number of features that indicated that they were not healthy. From their yeast screens, the researchers identified a protein called Nedd4 that reversed the pathologic features in these neurons.

Nedd4 is an E3 ubiquitin-protein ligase, which is a protein involved in the removal of old or damaged proteins from a cell. It is part of the garbage disposal process. Importantly, Nedd4 has been shown to label alpha synuclein for disposal (Click here to read more about this) and it is also present in Lewy Bodies – the circular clusters of proteins present in the brains of people with Parkinson’s disease. Importantly, it is a ‘druggable’ target. Nedd4 has been considered a therapeutic target for cancer (Click here to read more on this).

More recently (and following the passing of Prof Lindquist) the group has published two research reports back-to-back in the journal Cell Systems:

yeast-3

Title: Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways.
Authors: Khurana V, Peng J, Chung CY, Auluck PK, Fanning S, Tardiff DF, Bartels T, Koeva M, Eichhorn SW, Benyamini H, Lou Y, Nutter-Upham A, Baru V, Freyzon Y, Tuncbag N, Costanzo M, San Luis BJ, Schöndorf DC, Barrasa MI, Ehsani S, Sanjana N, Zhong Q, Gasser T, Bartel DP, Vidal M, Deleidi M, Boone C, Fraenkel E, Berger B, Lindquist S.
Journal: Cell Syst. 2017 Jan 25. pii: S2405-4712(16)30445-8.
PMID: 28131822 (This article is OPEN ACCESS if you would like to read it)

And:

chung2

Title: In Situ Peroxidase Labeling and Mass-Spectrometry Connects Alpha-Synuclein Directly to Endocytic Trafficking and mRNA Metabolism in Neurons.
Authors: Chung CY, Khurana V, Yi S, Sahni N, Loh KH, Auluck PK, Baru V, Udeshi ND, Freyzon Y, Carr SA, Hill DE, Vidal M, Ting AY, Lindquist S.
Journal: Cell Syst. 2017 Jan 25. pii: S2405-4712(17)30002-9.
PMID: 28131823

In these reports, Prof Lindquist and colleagues systematically mapped out molecular pathways underlying the toxic effects of alpha-synuclein. They applied their yeast derived 332 genes that impact alpha-synuclein toxicity, and linked them to multiple Parkinson’s-associated genes and druggable targets, using software called TransposeNet.

1-s2.0-S2405471216304458-fx1

Source: Cell

The investigators then validated some of the connections in human iPS cells derived from people with Parkinson’s disease, confirming that some of the Parkinson’s disease-related genetic interactions observed in yeast are ‘conserved’ (that is maintained across evolution) to humans. And these findings fully vindicated Prof Lindquist’s ‘crazy’ idea of using yeast cells to investigate neurodegenerative disease.

In the second report, the researchers identified 225 proteins in close physical proximity to alpha-synuclein in neurons using a new technique (called ascorbate peroxidase (APEX) labeling – let’s just say it’s complicated, but if you’d like to read more about it, Click here). Many of those 225 proteins were well known to the researchers being involved with activities in vesicles and synaptic terminals, where alpha synuclein is often found. But the researchers also found microtubule-associated proteins (including tau) rubbing shoulders with alpha-synuclein, as well as proteins involved with mRNA binding, processing, and translation (which they were not expecting). Thus, not only has Prof Lindquist’s yeast model of Parkinson’s disease provided us with novel therapeutic targets, but also opened new avenues of research related to alpha synuclein functioning.

And there is now a ‘yeast’ biotech company?

It is called Yumanity.

yumanity-screenshot2

Yumanity. Source: ScientificAmerican

Started in December 2014, with $45 million in funding, Yumanity is focused on determining new targets for neurodegenerative conditions in yeast cells, testing those new targets in human cells, and then moving towards clinical trials with the best candidates. To date, they have not announced any clinical trial candidates, but they working on compounds that are targeting the NEDD4 pathway in Parkinson disease (discussed above). We will be watching this company with great interest.

So what does it all mean?

Back in the early 2000s, Prof Lindquist and her team asked a simple but strange question:

Can we use our knowledge of yeast genetics to study neurodegeneration?

We now know that the answer is ‘yes’. The small single cell organism that most of us associate with baking and beer, shares enough genetics with us that we can use it as an assay for investigating molecular pathways involved with diseases of the brain. And in the not so distant future, this simple little organism may be providing us with new treatments and therapies for those diseases.

As we suggested at the start of this post, Prof Lindquist has left an amazing legacy. If Yumanity can move a new drug into clinical trials for Parkinson’s disease, it will only further strengthen that legacy.

Susan Lee Lindquist – June 5, 1949 to October 27, 2016

The banner for today’s post was sourced from NewEuropeans

New kiwi research in Parkinson’s disease

February 24, 2017February 27, 2017 ~ Simon ~ 1 Comment

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I really didn’t expect to be writing about Parkinson’s research being conducted in New Zealand again so quickly, but yesterday a new study was published which has a few people excited.

It presents evidence of how the disease may be spreading… using cells collected from people with Parkinson’s disease.

In today’s post we will review the study and discuss what it means for Parkinson’s disease.

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The South Island of NZ from orbit. Source: Sciencenews

We may have mentioned the protein Alpha synuclein once or twice on this blog.

For anyone familiar with the biology of Parkinson’s disease, alpha synuclein is a major player. It is either public enermy no.1 in the underlying pathology of this condition or else it is the ultimate ‘fall guy’, left standing in the crime scene holding the bloody knife.

Remind me, what is alpha synuclein?

Alpha synuclein is an extremely abundant protein in our brains – making up about 1% of all the proteins floating around in each neuron (one of the main types of cell in the brain).

In healthy brain cells, normal alpha synuclein is typically found just inside the surface of the membrane surrounding the cell body and in the tips of the branches extending from the cell (in structures called presynaptic terminals which are critical to passing messages between neurons).

And why is alpha synuclein important in Parkinson’s disease?

Genetic mutations account for 10-20% of the cases in Parkinson’s disease.

Five mutations in the alpha-synuclein gene have been identified which are associated with increased risk of Parkinson’s disease (A53T, A30P, E46K, H50Q, and G51D – these are coordinates for locations on the alpha synuclein gene). Rare duplication or triplication of the gene have also been associated with Parkinson’s disease.

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The structure of alpha synuclein protein – blue squares are mutations. Source: Mdpi

So genetically, alpha synuclein is associated with Parkinson’s disease. But it is also involved at the protein level.

In brains of many people with Parkinson’s disease, there are circular clumps of alpha synuclein (and other proteins) that collect inside cells. These clumps are called Lewy bodies. They are particularly abundant in areas of the brain that have suffered cell loss.

A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia

No one has ever seen the process of Lewy body formation, so all we can do is speculate about how these aggregates develop. Currently there is a lot of evidence supporting the idea that alpha synuclein can be passed between cells. Once inside the new cell, the alpha synuclein helps to seed the formation of new Lewy bodies, and this is how the disease is believed to progress.

The passing of alpha synuclein between brain cells. Source: Natur e

Exactly how alpha synuclein is being passed between cells is the topic of much research at the moment. There are many theories and some results implicating methods such as direct penetration, or via a particular receptor. Perhaps even by a small package called an exosome being passed between cells (see image above).

How this occurs in the Parkinson’s disease brain, however, is unknown.

And this (almost) brings us to the kiwi scientists.

Last years, a group of Swiss scientists demonstrated that alpha synuclein could be passed between cells via ‘nanotubes’ – tiny tubes connecting between cells. The outlined their observations and results in this article:

switzerland
Title: Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes.
Authors: Abounit S, Bousset L, Loria F, Zhu S, de Chaumont F, Pieri L, Olivo-Marin JC, Melki R, Zurzolo C.
Journal: EMBO J. 2016 Oct 4;35(19):2120-2138.
PMID: 27550960

The researchers who conducted this study were interested in tunneling nanotubes.

Yes, I know, ‘What are tunneling nanotubes?’

Tunneling nanotubes (also known as Membrane nanotubes or cytoneme are long protrusions extending from one cell membrane to another, allowing the two cells to share their contents. They can extend for long distances, sometimes over 100 μm – 0.1mm, but that’s a long way in the world of cells!

nanotubes

Tunneling nanotubes (arrows). Source: Wikipedia (and PLOSONE)

Previous studies had demonstrated that tunneling nanotubes can pass different infectious agents (HIV for example – click here to read more on this), supporting the idea that these structures could be a general conduit by certain diseases could be spreading.

nanotubes

A tunneling nanotube between two cells. Source: Pasteur

In their study the Swiss researchers found that alpha synuclein could be transferred between brain cells (grown in culture) via tunneling nanotubes. In addition, following that process of transfer, the alpha synuclein was able to induce the aggregation (or clumping) of the alpha synuclein in recipient cells.

A particularly interesting finding was that alpha synuclein appeared to encourage the appearance of tunneling nanotubes (there were more tunneling nanotubes apparent when cells produced more alpha synuclein). And the alpha synuclein that was being transferred was being passed on in ‘lysosomal vesicles’ – these are the rubbish bags of the cell (lysosomal vesicles are used to take proteins away for degradation).

Paints a rather insidious picture of the ‘ultimate fall guy’ huh!

And that image was made worse by the results published by the kiwis last night:

maurice

Title: α-synuclein transfer through tunneling nanotubes occurs in SH-SY5Y cells and primary brain pericytes from Parkinson’s disease patients
Authors: Dieriks BV, Park TI, Fourie C, Faull RL, Dragunow M, Curtis MA.
Journal: Scientific Reports, 7, Article number: 42984
PMID: 28230073 (This article is OPEN ACCESS if you would like to read it)

In their study, the New Zealand scientists extended the Swiss research by looking at cells collected from people with Parkinson’s disease. The researchers took human brain pericytes, which were derived from the postmortem brains of people who died with Parkinson’s disease.

And before you ask: pericytes are cells that wrap around the cells lining small blood vessels. They are important to the development of new blood vessels and maintaining the structural integrity of microvasculature.

aa-pericit4ub6b

A pericyte (blue) hugging a blood vessel (red). Source: Xvivo

Pericytes contain alpha synuclein precipitates like those seen in neurons, and the kiwi scientists demonstrated that pericytes too can transfer alpha synuclein via tunneling nanotubes to neighbouring cells – representing a non-neuronal method of transport.

They also found that the transfer through the tunneling nanotubes can be very rapid – within 30 seconds – and the transferred alpha synuclein can hang around for more than 72 hours, suggesting that it is difficult for the receiving cell to dispose of. The researchers did note that the transfer through tunneling nanotubes occurred only in small subset of cells, but that this could explain the slow progression of Parkinson’s disease over time.

What does it all mean?

In order for us to truly tackle Parkinson’s disease and bring it under control, we need to know how this slowly progressing neurodegenerative condition is spreading. Some researchers in New Zealand have provided evidence involving cells collected from people with Parkinson’s disease that indicates one method by which the disease could be passed from one cell to another.

Tiny tunnels between cells, allowing material to be shared, could explain how the disease slowly progresses. The scientists observed the Parkinson’s associated protein alpha synuclein being passed between cells and then hanging around for more than a few days.

This method of transfer was made more interesting because the New Zealand researchers reported that non-neuronal cells (Pericytes, collected from people with Parkinson’s disease) could also form tunneling nanotubes. This observation raises questions as to what role non-neuronal cells could be playing in Parkinson’s disease.

This line of questions will obviously be followed up in future research, as will efforts to determine if tunneling nanotubes are actually present in the human brain or simply biological oddities present only in the culture dish. Demonstrating nanotubes in the brain will be difficult, but it would provide us with solid evidence that this method of disease transfer could be a bonafide cause of disease spread.

We watch with interest for further work in this area.

FULL DISCLOSURE: The author of this blog is a kiwi… and proud of it. He is familiar with the researchers who have conducted this research, but has had no communication with them regarding the publishing of this post. He simply thought that the results of their study would be of interest to the Parkinson’s community.

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