At the end of each year, it is a useful practise to review the triumphs (and failures) of the past 12 months. It is an exercise of putting everything into perspective.
2017 has been an incredible year for Parkinson’s research.
And while I appreciate that statements like that will not bring much comfort to those living with the condition, it is still important to consider and appreciate what has been achieved over the last 12 months.
In this post, we will try to provide a summary of the Parkinson’s-related research that has taken place in 2017 (Be warned: this is a VERY long post!)
The number of research reports and clinical trial studies per year since 1817
As everyone in the Parkinson’s community is aware, in 2017 we were observing the 200th anniversary of the first description of the condition by James Parkinson (1817). But what a lot of people fail to appreciate is how little research was actually done on the condition during the first 180 years of that period.
The graphs above highlight the number of Parkinson’s-related research reports published (top graph) and the number of clinical study reports published (bottom graph) during each of the last 200 years (according to the online research search engine Pubmed – as determined by searching for the term “Parkinson’s“).
PLEASE NOTE, however, that of the approximately 97,000 “Parkinson’s“-related research reports published during the last 200 years, just under 74,000 of them have been published in the last 20 years.
That means that 3/4 of all the published research on Parkinson’s has been conducted in just the last 2 decades.
And a huge chunk of that (almost 10% – 7321 publications) has been done in 2017 only.
So what happened in 2017? Continue reading
Last Monday, a SpaceX rocket lifted off from the Florida peninsular on route to the International Space Station.
On board that craft was an experiment that could have big implications for Parkinson’s disease. It involves a Parkinson’s-associated protein called Leucine-rich repeat kinase 2 (or LRRK2).
In today’s post, we will discuss why we needed to send this protein into orbit.
The International Space Station. Source: NASA
When you look up at the sky tonight – if you look for long enough – you may well see a bright little object hurtling across the sky (Click here to learn more about how to track the International Space Station). Know that inside that bright little object passing over you there is currently some Parkinson’s disease-related research being conducted.
What is the International Space Station?
The International Space Station (or the ISS) is the largest human-made object that we have ever put into space. It is so big in fact that you can see it with the naked eye from Earth.
(How’s that for exciting viewing?)
The current space station is 73.3 metres (240 feet) long and 44.5 metres (146 feet) wide, weighing approximately 420 tonnes (924,740 lb), and it has been continuously occupied for 16 years and 289 days, making it the longest continuous human presence in low Earth orbit. The ISS travels at a speed of 7.67 km/second, maintains an altitude of between 330 and 435 km (205 and 270 mi), and completes 15.54 orbits per day (it has made over 102,000 orbits!).
The size of the the ISS compared to a Boeing Jumbo jet. Source: Reddit
First approved by President Ronald Reagan in 1984, it was not until November 1998 that the first components of the International space station were first launched into orbit. 36 shuttle flights were made to help build the station. The first crew members took up residence on the 2nd November 2000, and the station was completed in 2011. There is always 6 crew members on board – the current team are Expedition 52 – and it has been visited by 220 astronauts, cosmonauts and space tourists from 17 different nations since the project began.
Oh yeah, and if you want to see what it looks like on board the ISS, in 2015 the European Space Agency provided an interactive tour and earlier this year Google Maps added an interactive tour of the ISS.
The title of today’s post is written in jest – my job as a researcher scientist is to find a cure for Parkinson’s disease…which will ultimately make my job redundant! But all joking aside, today was a REALLY good day for the Parkinson’s community.
Last night (3rd August) at 23:30, a research report outlining the results of the Exenatide Phase II clinical trial for Parkinson’s disease was published on the Lancet website.
And the results of the study are good:while the motor symptoms of Parkinson’s disease subject taking the placebo drug proceeded to get worse over the study, the Exenatide treated individuals did not.
The study represents an important step forward for Parkinson’s disease research. In today’s post we will discuss what Exenatide is, what the results of the trial actually say, and where things go from here.
Last night, the results of the Phase II clinical trial of Exenatide in Parkinson’s disease were published on the Lancet website. In the study, 62 people with Parkinson’s disease (average time since diagnosis was approximately 6 years) were randomly assigned to one of two groups, Exenatide or placebo (32 and 30 people, respectively). The participants were given their treatment once per week for 48 weeks (in addition to their usual medication) and then followed for another 12-weeks without Exenatide (or placebo) in what is called a ‘washout period’. Neither the participants nor the researchers knew who was receiving which treatment.
At the trial was completed (60 weeks post baseline), the off-medication motor scores (as measured by MDS-UPDRS) had improved by 1·0 points in the Exenatide group and worsened by 2·1 points in the placebo group, providing a statistically significant result (p=0·0318). As you can see in the graph below, placebo group increased their UPDRS motor score over time (indicating a worsening of motor symptoms), while Exenatide group (the blue bar) demonstrated improvements (or a lowering of motor score).
Reduction in motor scores in Exenatide group. Source: Lancet
This is a tremendous result for Prof Thomas Foltynie and his team at University College London Institute of Neurology, and for the Michael J Fox Foundation for Parkinson’s Research who funded the trial. Not only do the results lay down the foundations for a novel range of future treatments for Parkinson’s disease, but they also validate the repurposing of clinically available drug for this condition.
In this post we will review what we know thus far. And to do that, let’s start at the very beginning with the obvious question:
So what is Exenatide?
In October 2015, researchers from Georgetown University announced the results of a small clinical trial that got the Parkinson’s community very excited. The study involved a cancer drug called Nilotinib, and the results were rather spectacular.
What happened next, however, was a bizarre sequence of disagreements over exactly what should happen next and who should be taking the drug forward. This caused delays to subsequent clinical trials and confusion for the entire Parkinson’s community who were so keenly awaiting fresh news about the drug.
Earlier this year, Georgetown University announced their own follow up phase II clinical trial and this week a second phase II clinical trial funded by a group led by the Michael J Fox foundation was initiated.
In todays post we will look at what Nilotinib is, how it apparently works for Parkinson’s disease, what is planned with the new trial, and how it differs from the ongoing Georgetown Phase II trial.
The FDA. Source: Vaporb2b
This week the U.S. Food and Drug Administration (FDA) has given approval for a multi-centre, double-blind, randomised, placebo-controlled Phase IIa clinical trial to be conducted, testing the safety and tolerability of Nilotinib (Tasigna) in Parkinson’s disease.
This is exciting and welcomed news.
What is Nilotinib?
Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML).
What does any that mean?
Basically, it is the drug that is used to treat a type of blood cancer (leukemia) when the other drugs have failed. It was approved for treating this cancer by the FDA in 2007.
Dipraglurant is a mGluR5 negative allosteric modulator (don’t panic, it’s not as complicated as it sounds).
In today’s post, we’ll explain what all of that means and look at the science behind this new treatment.
An example of a person with dyskinesia. Source: JAMA Neurology
For anyone familiar with Parkinson’s disease, they will know that long term use of the treatment L-dopa can lead to two possible outcomes:
- The treatment loses it’s impact, requiring ever higher doses to be administered
- The appearance of dykinesias
Now, not everyone taking L-dopa will be affected by both of these outcomes, but people with young, onset Parkinson’s disease do seem to be at risk of developing L-dopa induced dykinesias.
What are Dyskinesias?
Dyskinesias (from Greek: dys – abnormal; and kinēsis – motion, movement) are simply a category of movement disorders that are characterised by involuntary muscle movements. And they are certainly not specific to Parkinson’s disease.
As we have suggested above, they are associated in Parkinson’s disease with long-term use of L-dopa.
Below is a video of two legends: the late Tom Isaacs (who co-founded the Cure Parkinson’s Trust) and David Sangster (he founded www.1in20Parkinsons.org.uk). They were both diagnosed with Parkinson’s disease in their late 20’s. Tom, having lived with Parkinson’s for 20 years at the time of this video provides a good example of what dyskinesias look like:
As you can see, dyskinesias are a debilitating issue for anyone who suffers them.
How do dyskinesias develop in Parkinson’s disease?
Before being diagnosed and beginning a course of L-dopa, the locomotion parts of the brain in a person with Parkinson’s disease gradually becomes more and more inhibited. This increasing inhibition results in the slowness and difficulty in initiating movement that characterises this condition. A person with Parkinson’s may want to move, but they can’t.
They are akinetic (from
Drawing of an akinetic individual with Parkinson’s disease, by Sir William Richard Gowers
L-dopa tablets provide the brain with the precursor to the chemical dopamine. Dopamine producing cells are lost in Parkinson’s disease, so replacing the missing dopamine is one way to treat the motor features of the condition. Simply giving people pills of dopamine is a non-starter: dopamine is unstable, breaks down too quickly, and (strangely) has a very hard time getting into the brain. L-dopa, on the other hand, is very robust and has no problem getting into the brain.
Sinemet is L-dopa. Source: Drugs
Once inside the brain, L-dopa is quickly converted into dopamine. It is changed into dopamine by an enzyme called DOPA decarboxylase, and this change rapidly increases the levels of dopamine in the brain, allowing the locomotion parts of the brain to function more normally.
The chemical conversion of L-dopa to dopamine. Source: Nootrobox
In understanding this process, it is important to appreciate that when an L-dopa tablet is consumed and L-dopa enters the brain, there is a rapid increase in the levels of dopamine. A ‘spike’ in the supply of dopamine, if you will, and this will last for the next few hours, before the dopamine is used up.
As the effects of the L-dopa tablet wear off, another tablet will be required. This use of multiple L-dopa pills across the day gives rise to a wave-like shape to the dopamine levels in the brain over the course of the day (see the figure below). The first pill in the morning will quickly lift the levels of dopamine enough that the individual will no longer feel akinetic. This will allow them to be able to function with normal controlled movement for several hours before the L-dopa begins to wear off. As the L-dopa wears off, the dopamine levels in the brain drop back towards levels that will leave the person feeling akinetic and at this point another L-dopa tablet is required.
After several years of L-dopa use, many people with Parkinson’s disease will experience a weaker response to each tablet. They will also find that they have more time during which they will be unable to move (exhibiting akinesia). This is simply the result of the progression of Parkinson’s disease – L-dopa treats the motor features of the disease but only hides/masks the fact that the disease is still progressing.
To combat this shorter response time, the dose of L-dopa is increased. This will result in increasing levels of dopamine in the brain (as illustrated by the higher wave form over time in the image below). It will take more L-dopa medication induced dopamine to lift the individual out of the akinetic state.
This increasing of L-dopa dosage, however, is often associated with the gradual development of abnormal involuntary movements that appear when the levels of L-dopa induced dopamine are the highest.
These are the dyskinesias.
Are there different types of dyskinesias?
Yes there are.
Dyskinesias have been broken down into many different subtypes, but the two main types of dyskinesia are:
Chorea – these are involuntary, irregular, purposeless, and unsustained movements. To an observer, Chorea will look like a very disorganised/uncoordinated attempt at dancing (hence the name, from the Greek word ‘χορεία’ which means ‘dance’). While the overall activity of the body can appear continuous, the individual movements are brief, infrequent and isolated. Chorea can cause problems with maintaining a sustained muscle contraction, which may result in affected people dropping things or even falling over.
Dystonia – these are sustained muscle contractions. They often occur at rest and can be either focal or generalized. Focal dystonias are involuntary contractions in a single body part, for example the upper facial area. Generalized dystonia, as the name suggests, are contraction affecting multiple body regions at the same time, typically the trunk, one or both legs, and another body part. The intensity of muscular movements in sufferers can fluctuate, and symptoms usually worsen during periods of fatigue or stress.
We have previously discussed the current treatment options for dyskinesias (click here to see that post).
Ok, so what clinical trials are Addex Therapeutics and the Michael J Fox Foundation preparing and why?
They are preparing to take a drug called Dipraglurant through phase III testing for L-dopa inducing dyskinesias in Parkinson’s disease. Dipraglurant is a mGluR5 negative allosteric modulator.
And yes, I know what you are going to ask next: what does any of that mean?
Ok, so mGluR5 (or Metabotropic glutamate receptor 5) is a G protein-coupled receptor. This is a structure that sits in the skin of a cell (the cell membrane), with one part exposed to the outside world – waiting for a chemical to bind to it – while another part is inside the cell, ready to act when the outside part is activated. The outside part of the structure is called the receptor.
Metabotropic receptors are a type of receptor that is indirectly linked with channels in cell membrane. These channels open and close, allowing specific elements to enter the cell. When a chemical (or agonist) binds to the receptor and it becomes activated, the part of the structure inside the cell will send a signal to the channel via a messenger (called a G-protein).
The chemical that binds to mGluR5 is the neurotransmitter glutamate.
Metabotropic glutamate receptor 5 activation. Source: Nature
But what about the “negative allosteric modulator” part of ‘mGluR5 negative allosteric modulator’
This is the key part of this new approach. Allosteric modulators are a new class of orally available small molecule therapeutic agents. Traditionally, most marketed drugs bind directly to the same part of receptors that the body’s own natural occurring proteins attach to. But this means that those drugs are competing with those endogenous proteins, and this can limit the potential effect of the drug.
Allosteric modulators get around this problem by binding to a different parts of the receptor. And instead of simply turning on or off the receptor, allosteric modulators can either turn up the volume of the signal being sent by the receptor or decrease the signals. This means that when the body’s naturally occurring protein binds in the receptor, allosteric modulators can either amplify the effect or reduce it depending on which type of allosteric modulators is being administered.
How Allosteric modulators work. Source: Addrex Thereapeutics
There are two different types of allosteric modulators: positive and negative. And as the label suggests, positive allosteric modulators (or PAMs) increase the signal from the receptor while negative allosteric modulators (or NAMs) reduce the signal.
So Dipraglurant turns down the volume of the signal from the mGluR5 receptor?
By turning down the volume of the glutamate receptor mGluR5, researchers believe that we can reduce the severity of dyskinesias.
But hang on a second. Why are we looking at glutamate in dyskinesias? Isn’t dopamine the chemical of interest in Parkinson’s disease?
So almost 10 years ago, some researchers noticed something interesting in the brains of Parkinsonian monkeys that had developed dyskinesias:
Title: mGluR5 metabotropic glutamate receptors and dyskinesias in MPTP monkeys.
Authors: Samadi P, Grégoire L, Morissette M, Calon F, Hadj Tahar A, Dridi M, Belanger N, Meltzer LT, Bédard PJ, Di Paolo T.
Journal: Neurobiol Aging. 2008 Jul;29(7):1040-51.
The researchers conducting this study induced Parkinson’s disease in monkeys using a neurotoxin called MPTP, and they then treated the monkeys with L-dopa until they began to develop dyskinesias. At this point when they looked in the brains of these monkeys, the researchers noticed a significant increase in the levels of mGluR5, which was associated with the dyskinesias. This finding led the researchers to speculate that reducing mGluR5 levels might reduce dyskinesias.
And it did!
Subsequent preclinical research indicated that targeting mGluR5 might be useful in treating dyskinesias, especially with negative allosteric modulators:
Title: The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model
Authors: Bezard E, Pioli EY, Li Q, Girard F, Mutel V, Keywood C, Tison F, Rascol O, Poli SM.
Journal: Mov Disord. 2014 Jul;29(8):1074-9.
In this study, the researchers tested the efficacy of dipraglurant in Parkinsonian primates that had developed L-dopa induced dyskinesias. They tested three different doses of the drug (3, 10, and 30 mg/kg).
Dipraglurant significantly reduced dyskinesias in the monkeys, with best effect being reached using the 30 mg/kg dose. Importantly, the dipraglurant treatment had no impact on the efficacy of L-dopa which was still being used to treat the monkeys Parkinson’s features.
This research lead to a clinical trials in man, and last year Addex Therapeutics published the results of their phase IIa clinical trial of Dipraglurant (also called ADX-48621):
Title: A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson’s Disease.
Authors: Tison F, Keywood C, Wakefield M, Durif F, Corvol JC, Eggert K, Lew M, Isaacson S, Bezard E, Poli SM, Goetz CG, Trenkwalder C, Rascol O.
Journal: Mov Disord. 2016 Sep;31(9):1373-80.
The Phase IIa double-blind, placebo-controlled, randomised trial was a dose escalation study, conducted in 76 patients with Parkinson’s disease L-dopa-induced dyskinesia – 52 subjects were given dipraglurant and 24 received a placebo treatment. The dose escalation assessment of dipraglurant started at 50 mg once daily to 100 mg 3 times daily. The study was conducted over 4 weeks.
The investigators found that dipraglurant significantly reduced the dyskinesias on both day 1 of the study and on day 14, and this treatment did not result in any worsening of the Parkinsonian features. And remember that this was a double blind study, so both the investigators and the participants had no idea which treatment was being given to each subject. Thus little bias can influence the outcome, indicating that dipraglurant really is having a beneficial effect on dyskinesias.
The company suggested that dipraglurant’s efficacy in reducing L-dopa-induced dyskinesia warrants further investigations in a larger number of patients. And this is what the company is now doing with the help of the Michael J. Fox Foundation (MJFF). In addition, dipraglurant’s potential benefits on dystonia are also going to be investigated with support from the Dystonia Medical Research Foundation (DMRF).
And the really encouraging aspect of this research is that Addex Therapeutics are not the only research group achieving significant beneficial results for dykinesias using this treatment approach (click here to read about other NAM-based clinical studies for dyskinesias).
Fingers crossed for more positive results here.
What happens next?
L-dopa induced dyskinesias can be one of the most debilitating aspects of living with Parkinson’s disease, particularly for the early-onset forms of the condition. A great deal of research is being conducted in order to alleviate these complications, and we are now starting to see positive clinical results starting to flow from that research.
These results are using new type of therapeutic drug that are designed to increase or decrease the level of a signal occurring in a cell without interfering with the normal functioning of the chemicals controlling the activation of that signal.
This is really impressive biology.
The banner for today’s post was sourced from Steam
A build up of a protein called alpha synuclein inside neurons is one of the characteristic feature of the Parkinsonian brain. This protein is believed to be partly responsible for the loss of dopamine neurons in this condition.
A similar build up of alpha synuclein is also seen in the deadly skin cancer, Melanoma… but those cells don’t die (?!?)… in fact, they just keep on dividing.
Why is there this critical difference?
In today’s post we look at an interesting new study that may have solved this mystery.
A melanoma. Source: Huffington Post
Parkinson’s disease has a very strange relationship with the skin cancer melanoma.
As we have stated in previous posts (Click here, here, here and here to read those posts) people with Parkinson’s disease are 2-8 times more likely to develop melanoma than people without Parkinson’s (And this finding has been replicated a few times: Olsen et al, 2005; Olsen et al, 2006; Driver et al 2007; Gao et al 2009; Lo et al 2010; Bertoni et al 2010;Schwid et al 2010; Ferreira et al, 2010; Inzelberg et al, 2011; Liu et al 2011; Kareus et al 2012; Wirdefeldt et al 2014; Catalá-López et al 2014; Constantinescu et al 2014; Ong et al 2014).
The truly baffling detail in this story, however, is that this relationship is reciprocal – if you have melanoma you are almost 3 times more likely to develop Parkinson’s disease than someone without melanoma (Source: Baade et al 2007; Gao et al 2009).
What is melanoma exactly?
Melanoma is a type of skin cancer.
It develops from the pigment-containing cells known as melanocytes. Melanocytes are melanin-producing cells located in the bottom layer (the stratum basale) of the skin’s outer layer (or epidermis).
The location of melanocytes in the skin. Source: Wikipedia
Melanocytes produce melanin, which is a pigment found in the skin, eyes, and hair. It is also found in the brain in certain types of cells, such as dopamine neurons (where it is referred to as neuromelanin).
Neuromelanin (brown) in dopamine neurons. Source: Schatz
Melanomas are usually caused by DNA damage resulting from exposure to ultraviolet radiation. Ultraviolet radiation from tanning beds increases the risk of melanoma (Source), as does excessive air travel (Source), or simply spending to much time sun bathing.
Approximately 2.2% of men and women will be diagnosed with melanoma at some point during their lives (Source). In women, melanomas most commonly occur on the legs, while in men they are most common on the back. Melanoma makes up 5% of all cancers (Source).
Generally, melanomas is one of the safer cancers, as it can usually be detected early by visual inspection. This cancer is made dangerous, however, by its ability to metastasise (or spread to other organs in the body).
The stages of melanoma. Source: Pathophys
Are there any genetic associations between Parkinson’s disease and melanoma?
When the common genetics mutations that increase the risk of both conditions were previously analysed, it was apparent that none of the known Parkinson’s mutations make someone more susceptible to melanoma, and likewise none of the melanoma-associated genetic mutations make a person vulnerable to Parkinson’s disease (Meng et al 2012;Dong et al 2014; Elincx-Benizri et al 2014).
In fact, researchers have only found very weak genetic connections between two conditions (Click here to read our previous post on this). It’s a real mystery.
Are there any other connections between Parkinson’s disease and melanoma?
Another shared feature of both Parkinson’s disease and melanoma is the build up of a protein called alpha synuclein. Alpha synuclein is believed to be one of the villains in Parkinson’s disease – building up inside a cell, becoming toxic, and eventually killing that cell.
But recently researchers noticed that melanoma also has a build up of alpha synuclein, but those cells don’t die:
Title: Parkinson’s disease-related protein, alpha-synuclein, in malignant melanoma
Authors: Matsuo Y, Kamitani T.
Journal: PLoS One. 2010 May 5;5(5):e10481.
PMID: 20463956 (This article is OPEN ACCESS if you would like to read it)
In this study, researchers from Japan found that alpha synuclein was detected in 86% of the primary and 85% of the metastatic melanoma. Understand that the protein is not detectable in the non-melanoma cancer cells.
So what is it doing in melanoma cells?
Recently, researchers from Germany believe that they have found the answer to this question:
Title: Treatment with diphenyl-pyrazole compound anle138b/c reveals that α-synuclein protects melanoma cells from autophagic cell death
Authors: Turriani E, Lázaro DF, Ryazanov S, Leonov A, Giese A, Schön M, Schön MP, Griesinger C, Outeiro TF, Arndt-Jovin DJ, Becker D
Journal: Proc Natl Acad Sci U S A. 2017 Jun 5. pii: 201700200. doi: 10.1073/pnas.1700200114
In their study, the German researchers looked at levels of alpha synuclein in melanoma cells. They took the melanoma cells that produced the most alpha synuclein and treated those cells with a chemical that inhibits the toxic form of alpha synuclein (which results from the accumulation of the protein).
What they observed next was fascinating: the cell morphology (or physically) changed, leading to massive melanoma cell death. The investigators found that this cell death was caused by instability of mitochondria and a major dysfunction in the autophagy process.
Mitochondria, you may recall, are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.
Mitochondria and their location in the cell. Source: NCBI
Autophagy is the garbage disposal/recycling process within each cell, which is an absolutely essential function. Without autophagy, old proteins and mitochondria will pile up making the cell sick and eventually it dies. Through the process of autophagy, the cell can break down the old protein, clearing the way for fresh new proteins to do their job.
The process of autophagy. Source: Wormbook
Waste material inside a cell is collected in membranes that form sacs (called vesicles). These vesicles then bind to another sac (called a lysosome) which contains enzymes that will breakdown and degrade the waste material. The degraded waste material can then be recycled or disposed of by spitting it out of the cell.
What the German research have found is that the high levels of alpha synuclein keep the mitochondria stable and the autophagy process working at a level that helps to keeps the cancer cell alive.
Next, they replicated this cell culture research in mice with melanoma tumors. When the mice were treated with the chemical that inhibits the toxic form of alpha synuclein, the cancer cancer became malformed and the autophagy process was blocked.
The researchers concluded that “alpha synuclein, which in PD exerts severe toxic functions, promotes and thereby is highly beneficial to the survival of melanoma in its advanced stages”.
So what does all of this mean for Parkinson’s disease?
Well, this is where the story gets really interesting.
You may be pleased to know that the chemical (called Anle138b) which was used to inhibit the toxic form of alpha synuclein in the melanoma cells, also works in models of Parkinson’s disease:
Title: Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease.
Authors: Wagner J, Ryazanov S, Leonov A, Levin J, Shi S, Schmidt F, Prix C, Pan-Montojo F, Bertsch U, Mitteregger-Kretzschmar G, Geissen M, Eiden M, Leidel F, Hirschberger T, Deeg AA, Krauth JJ, Zinth W, Tavan P, Pilger J, Zweckstetter M, Frank T, Bähr M, Weishaupt JH, Uhr M, Urlaub H, Teichmann U, Samwer M, Bötzel K, Groschup M, Kretzschmar H, Griesinger C, Giese A.
Journal: Acta Neuropathol. 2013 Jun;125(6):795-813
PMID: 23604588 (This article is OPEN ACCESS if you would like to read it)
In this first study the researchers discovered Anle138b by conducted a large screening study to identify for molecules that could inhibit the toxic form of alpha synuclein.
They next tested Anle138b in both cell culture and rodent models of Parkinson’s disease and found it to be neuroprotective and very good at inhibiting the toxic form of alpha synuclein. And the treatment looks to be very effective. In the image below you can see dark staining of toxic alpha synuclein in the left panel from the brain of an untreated mouse, but very little staining in the right panel from an Anle138b treated mouse.
Toxic form of alpha synuclein (dark staining). Source: Max-Planck
Importantly, Anle138b does not interfere with normal behaviour of alpha synuclein in the mice (such as production of the protein, correct functioning, and eventual degradation/disposal of the protein), but it does act as an inhibitor of alpha synuclein clustering or aggregation (the toxic form of the protein). In addition, the investigators found no toxic effects of Anle138b in any of their experiments even after long-term high-dose treatment (more than one year).
And in a follow up study, the drug was effective even if it was given after the disease model had started:
Title: The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset
Authors: Levin J, Schmidt F, Boehm C, Prix C, Bötzel K, Ryazanov S, Leonov A, Griesinger C, Giese A.
Journal: Acta Neuropathol. 2014 May;127(5):779-80.
PMID: 24615514 (This article is OPEN ACCESS if you would like to read it)
During the first study, the researchers had started Anle138b treatment in the mouse model of Parkinson’s disease at a very young age. In this study, however, the investigators began treatment only as the symptoms were starting to show, and Anle138b was found to significantly improve the overall survival of the mice.
One particularly interesting aspect of Anle138b function in the brain is that it does not appear to change the level of the autophagy suggesting that the biological effects of treatment with Anle138b is cell-type–specific (Click here to read more about this). In cancer cells, it is having a different effect to that in brain cells. These differences in effect may also relate to disease conditions though, as Anle138b was not neuroprotective in a mouse model of Multiple System Atrophy (MSA; Click here to read more about this).
Is Anle138b being tested in the clinic?
Ludwig-Maximilians-Universität München and the Max Planck Institute for Biophysical Chemistry (Göttingen) have spun off a company called MODAG GmbH that is looking to advance Anle138b to the clinic (Click here for the press release). The Michael J Fox Foundation are helping to fund more preclinical development of this treatment (Click here to read more about this).
We will be watching their progress with interest.
What does it all mean?
Summing up: There are many mysteries surrounding Parkinson’s disease, but some researchers from Germany may have just solved one of them and at the same time developed a potentially useful new treatment.
They have discovered that the Parkinson’s associated protein, alpha synuclein, which is produced in large amounts in the skin cancer melanoma, is actually playing an important role in keeping those cancer cells alive. By finding a molecule that can block the build up of alpha synuclein, they have not only found a treatment for melanoma, but also potentially one for Parkinson’s disease.
And given that both diseases are closely associated, this could be seen as a great step forward. Two birds with one stone as the saying goes.
The banner for today’s post was sourced from Wikipedia
Today’s post is something a bit different from our usual fodder.
Here at SoPD HQ, we like to throw our support behind worthy projects. And we were recently contacted by Eirwen Malin regarding an idea that we were genuinely passionate about: Improving patient education
Eirwen is being supported by the Winston Churchill Memorial Trust and in the second half of the year she will travel to the USA and then later to Argentina to find new ideas for Patient Education.
In today’s post, we are handing over the keys to the car to Eirwen and we will let her explain the project that she is about to undertake. The goal of this post is to get feedback, ideas and thoughts about the plans for her project. We also encourage all our readers to follow Eirwen (contact details at the bottom of the post) as she undertakes this exciting endeavour.
Hello, this is me – Eirwen Malin. I’m not prepared to own up to quite how many years I worked in the Third sector in Wales but take it from me (and my photo) quite a lot. I worked mostly trying to influence policy and practice, advocating on behalf of a range of different groups and issues, researching, running demonstration projects, that type of thing. Trying to get the issues heard above the clamour and competing for funding which would hopefully make a difference.
In 2014 I was diagnosed with Parkinson’s and life changed a lot.
It took me a while to realise it but apart from threatening my physical voice, (it’s suggested that 75-90% of people with Parkinson’s have some sort of voice, speech or communication difficulties, see here for more information) having Parkinson’s gave me a new and more powerful voice. I could now speak with the authority of “lived experience”, which might help me make a difference for me and my fellow Parkies.
My own experience of diagnosis was not good. I’d been referred to a neurologist to “put my mind at rest”, so it was completely unexpected. I was not diagnosed by a PD specialist and had to be referred on to a clinic, I was told what I needed was information and then sent off to wait for an appointment with no phone number, website address, fact sheet, nothing!
While I waited, for nearly 6 months, I found masses of information, some of it well expressed and clear, some incomprehensible, some coming from authoritative sources, some from people who were living with the condition, some contradictory, some pseudo-scientific, some completely off the wall yet plausible, in short a potential minefield! Now I am a reasonably competent person, who quite enjoys and is able to read and make sense of research papers, understand the statistics, weigh up the arguments and generally make sense of what’s available. However lots of people with Parkinson’s will not be like me.
So, now I thought maybe I could use my new voice to shout out for the need for Patient Education.
I signed up as a volunteer facilitator for Parkinson’s UK’s Self-Management Programme.
It’s an excellent course, based on work long championed by Dr Kate Lorig at Stanford:
I have seen it help people to gain confidence and regain a measure of control over their lives. I would thoroughly recommend it, however, 6 half day sessions can’t provide the on-going information about medical, social and lifestyle adjustments that are required to live as well as possible with Parkinson’s. Sometimes one needs almost daily updates to manage the complex and peskily changing symptoms. After all the patient is the only one who is there 24/7/365! They must know where to find information and importantly what questions to ask. I meet far too many people desperately seeking guidance.
The opportunity arose to apply for a Winston Churchill Travel Fellowship, as the strapline says the idea is “Travel to learn – return to inspire”.
Established in 1965, following the death of Sir Winston Churchill, the Winston Churchill Memorial Trust hands out 150 fellowships each year providing a unique opportunity for UK citizens to travel overseas with the goal of bringing back fresh ideas and new solutions to today’s issues, for the benefit of others in the UK.
At the end of a quite lengthy application process which has whittled over 1000 application down to about 150 Fellowships I feel very honoured, “Yippee”, to have been successful in the Medical Practice and Education category alongside a CEO of an NHS Trust, Doctors, Nurses, Researchers etc, Yikes!
My quest is to find new ideas for Patient Education. I am focussing particularly in the field of degenerative neurological conditions. This area is particularly tricky because I think it’s reasonable to say that even the experts still have much to learn and the multi-faceted nature of the conditions and their symptoms result in the need for a team of medical practitioners to support the patient making it even more difficult to provide consistent information. The patient has to know whats going on.
For my fellowship, I will be travelling to USA and Argentina.
Yippee, exciting trips, but once again Yikes, the journeys are long, I’ll get even stiffer, and I don’t do well in crowds or queues. It’s a good job that my partner can come and help with the stressful bits.
I’ve tried to cover as many perspectives as I can think of but I’d welcome ideas from readers. I’ll try to fit them in.
A bit more detail on the US trip July-August 2017.
A meeting with the Michael J Fox Foundation. I found lots of information on their website, it seems like a good place to start.
I’m hoping to visit New York University’s Electronic Media Patient Education Initiative but still waiting for confirmation
I’m excited to be going to visit Dance for PD in Brooklyn. They do some fantastic work getting people moving and I’m sure there is much to learn.
I’ll be talking with the charismatic David Leventhal and other staff to ask how they see their educational role. Most important I want to get feedback from their participants. I have developed a one-woman storytelling performance Sorting the Sock Drawer which I will use to stimulate discussion.
San Francisco area
I’m going to see Dr Kate Lorig (mentioned above) and hoping to talk to some people who will be at Stanford on a one-week course.
University of California San Francisco Parkinson’s Disease Clinic and Research Centre. Really clearly written information on their website that I wish I had found earlier.
By the way I’ll be packing my cheesecloth tunic and flares – it’s the 50th anniversary of the “Summer of Love” with apologies to younger readers who don’t remember!
I will meet Professor Cynthia McRae, a behavioural psychologist who focusses on the impact of non-medical symptoms such as quality of life, depression, loneliness, and other psychological factors that are often associated with Parkinson’s disease, but are not always included within medical research.
Professor Cynthia McRae
She said “If there is such a thing as a good place to have Parkinson’s then Denver is it!” and introduced me to the Parkinson’s Association of the Rockies. They have so much going on I shall spend some time with them. Once again I’ll be using my performance to stimulate a discussion.
A flying visit to spend a day with the Parkinson’s Voice Project, their mantra about people with Parkinson’s living “with intent” really speaks to me.
Pittsburgh and around
University of Pittsburgh Institute for Neurodegenerative Diseases to be confirmed
I will visit the Wheeling Hospital Parkinson’s Education Centre. Also at Wheeling I will be filling a gap in the schedule to speak with general medical practitioners to ask about issues for them in helping patients with neurodegenerative conditions
Finally Health Plan, in St Clairesville Ohio. Health Plan is a not-for profit health insurance provider that calls itself a health maintenance organisation. It will be interesting to get a business perspective on Patient Education.
Alongside the formal meetings I hope to just talk to people I meet, tell them what I am doing and get their views. In the end that might be as important as the planned programme.
Planning for Argentina in Oct-Nov still to be finalised.
So once again Yippee it’s going to be fascinating and exciting but Yikes I really do hope I can come home with the goods and help influence the provision of a better system of educating patients than I encountered. I feel the sense of responsibility to the Winston Churchill Memorial Trust who have invested faith and funds in my idea and my ability to deliver and even more so to my fellow Parkies diagnosed or not for whom I’d like to make a difference.
I’ll be posting activities, photos, videos of the formal meetings and the more touristy parts of the trips on facebook https://www.facebook.com/EirwenWCTF you can follow my activities, send me messages there os send messages via e-mail email@example.com
In December 2016, Parkinson’s UK produced a wonderful series of video explaining some of the basics of Parkinson’s disease. They are a really useful resources for folks who would like to better understand this condition, but are not really interested in the hard-core science. You can find them on Parkinson’s UK Youtube channel, but we present a couple of them here to give you a taster. Enjoy.
1. What is Parkinson’s disease?
2. How does the medication work?
3. How are future drugs developed?
1. An explanation of the clinical trial process:
2. The process of getting a drug from the lab bench to the market:
Performer Miley Cyrus says that “Pink isn’t just a colour, it’s an attitude!”
Whether that is true or not is not for us to say.
What we can tell you is that ‘Pink’ is also a gene which is associated with Parkinson’s disease. And not just any form of Parkinson’s disease – people with early onset Parkinson’s (diagnosed before 40 years of age) often have specific mutations in this gene. And recently there has been new research published which may help these particular individuals.
Today’s post will review the new research and look at what it means for people with early onset Parkinson’s disease.
The actor Michael J Fox requires no introduction.
Especially in the Parkinson’s community where his Michael J Fox Foundation has revolutionised the funding and supporting of Parkinson’s disease research (INCREDIBLE FACT: Since 2000, The Michael J. Fox Foundation has funded more than US$450 MILLION of Parkinson’s disease research) and is leading the charge in the search for a cure for this condition.
Mr Fox has become one of the foremost figures in raising awareness about the disease that he himself was diagnosed with at just 29 years of age.
Wow, so young?
It is a common mistake to consider Parkinson’s disease a condition of the aged portion of society. While the average age of diagnosis floats around 65 years of age, it is only an average. The overall range of that extends a great distance in both directions.
Being diagnosed so young, Mr Fox would be considered to have early onset Parkinson’s disease.
What is early onset Parkinson’s disease?
Broadly speaking there are three basic divisions of Parkinson’s disease across different age ranges:
- Juvenile-onset Parkinson disease – onset before age 20 years
- Early-onset Parkinson disease – before age 50 years
- Late-onset Parkinson disease – after age 50 years is considered
The bulk of people with Parkinson’s disease are considered ‘late-onset’. The Juvenile-onset version of the condition, on the other hand, is extremely rare but cases do pop up regularly in the media (For example, click here). We have previously written about Juvenile-onset Parkinson disease (Click here for that post).
Early-onset Parkinson disease is more common than the juvenile form, but still only makes up a fraction of the overall Parkinsonian population. Some of those affected call themselves 1 in 20 as this is considered by some the ratio of early-onset Parkinson’s compared to late-onset.
How prevalent is early onset Parkinson’s?
In 2009, Parkinson’s UK published a report on the prevalence of Parkinson’s disease in the UK.
Using the General Practice Research Database (GPRD), which houses information about 7.2% of the UK population (or 3.4 million people in 2009), Parkinson’s UK found that the frequency of Parkinson’s disease in the general public was 27 cases in every 10,000 people (or 1 person in every 370 of the general population). The prevalence is higher in men (31 in every 10,000 compared to 24 in every 10,000 among females)
As you can see from the table above, the number of people affected by early onset Parkinson’s disease is small when compared to the late-onset population.
Officially, the prevalence of early onset Parkinson’s in Europe is estimated to be 1 in every 8,000 people in the general population (Source: Orphanet). This makes the population of affected individuals approximately 5-10 % of all people with Parkinson’s. Hence the 1 in 20 label mentioned above.
Like older onset Parkinson’s, males are more affected than females (1.7 males to every 1 female case). In addition, women generally develop the disease two years later than men.
So what does ‘Pink’ have to do with early onset Parkinson’s?
First, let’s have a look at ‘Pink’ the gene.
PTEN-induced putative kinase 1 (or PINK1; also known as PARK6) is a gene that is thought to protect cells. Specifically, Pink1 is believed to interact with another Parkinson’s disease-associated protein called Parkin (also known as PARK2). Pink1 grabs Parkin and causes it to bind to dysfunctional mitochondria. Parkin then signals to the rest of the cell for that particular mitochondria to be disposed of. This is an essential part of the cell’s garbage disposal system.
Hang on a second. Remind me again: what are mitochondria?
Mitochondria are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.
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.
When a cell is stressed by a toxic chemical, the organisation of mitochondria breaks down (as is shown in the image below, where everything except mitochondria (in green) and the nucleus (blue) has been made invisible:
Mitochondria (green) in health cells (left) and in unhealthy cells (right).
The nucleus of the cell is in blue. Source: Salk Institute
In normal, healthy cells, PINK1 is absorbed by mitochondria and eventually degraded. In unhealthy cells, however, this process is inhibited and PINK1 starts to accumulate on the outer surface of the mitochondria. There, it starts grabbing the PARKIN protein. This pairing is a signal to the cell that this particular mitochondria is not healthy and needs to be removed.
Pink1 and Parkin in normal (right) and unhealthy (left) situations. Source: Hindawi
The process by which mitochondria are removed is called autophagy. Autophagy is an absolutely essential function in a cell. Without it, old proteins will pile up making the cell sick and eventually it dies. Through the process of autophagy, the cell can break down the old protein, clearing the way for fresh new proteins to do their job.
Think of autophagy as the waste disposal process of the cell.
So why is Pink1 important to Parkinson’s disease?
In 2004 this research article was published:
Title: Hereditary early-onset Parkinson’s disease caused by mutations in PINK1
Authors: Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW.
Journal: Science. 2004 May 21;304(5674):1158-60.
The researchers in this study were the first to report that mutations in the Pink1 gene were associated with increased risk of Parkinson’s disease. They found three families in Europe that exhibited a very similar kind of Parkinson’s disease and by analysing their DNA they determined that mutations in the Pink1 gene were directly linked to the condition.
They also looked at where in the cell Pink1 protein was located, noting the close contact with the mitochondria. In addition, they noted that the normal Pink1 protein provided the cell with protection against a toxic chemical, while the mutated version of Pink1 did not. These findings led the researchers to conclude that Pink1 and mitochondria may be involved in the underlying mechanisms of Parkinson’s disease.
And this initial study was quickly followed up 7 months later by this report:
Title: Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease.
Authors: Rogaeva E, Johnson J, Lang AE, Gulick C, Gwinn-Hardy K, Kawarai T, Sato C, Morgan A, Werner J, Nussbaum R, Petit A, Okun MS, McInerney A, Mandel R, Groen JL, Fernandez HH, Postuma R, Foote KD, Salehi-Rad S, Liang Y, Reimsnider S, Tandon A, Hardy J, St George-Hyslop P, Singleton AB.
Journal: Arch Neurol. 2004 Dec;61(12):1898-904.
In this study, the researchers analysed the Pink1 gene in 289 people with Parkinson’s disease and 80 neurologically normal control subjects. They identified 27 genetic variations, including a mutation in 2 unrelated early-onset Parkinson disease patients. They concluded that autosomal recessive mutations in PINK1 result in a rare form of early-onset Parkinson’s disease.
What does autosomal recessive mean?
Autosomal recessive means two copies of an abnormal gene must be present in order for the disease or trait to develop. That is to say, both parents will be carrying one copy of the mutation.
Mutations in the Pink1 gene have now been thoroughly analysed, with many mutations identified (the red and blue arrows in the image below). It is important, however, to understand that not all of those mutations are associated with Parkinson’s disease.
Looks complicated. Genetic variations in the Pink1 gene. Source: APS
So how do mutations in the Pink1 gene cause Parkinson’s disease?
We believe that the mutations in the Pink1 DNA result in malformed Pink1 protein. This results in Pink1 not being able to do what it is supposed to do. You will remember what we wrote above: Pink1 grabs Parkin when mitochondria get sick and Parkin signals for that mitochondria is be disposed of. Well, in the absence a properly functioning Pink1, we believe that there is a build up of sick mitochondria and this is what kills off the cell. All Parkinson’s disease-associated mutations in the Pink1 gene inhibit the ability of Pink1 grab parkin (Click here for more on this).
And we see this in flies.
Flies. Source: TheConservation
Flies (or drosophila) are a regular feature in biological research. Given their short life cycle, they can be used to quickly determine the necessity and function of particular genes. Yes, they are slightly different to us, but quite often the same biological principles apply.
Take Pink1 for example.
When scientists mutate the Pink1 gene in flies, it leads to the loss of flight muscles and male sterility. These effects both appear to be due to the kind of mitochondrial issues we were discussing above. One really amazing fact is that the human version of Pink1 can actually rescue the flies that have their Pink1 gene mutated. This is remarkable because across evolution genes begin to differ slightly resulting in some major differences by the time you get to humans. The fact that Pink1 is similar between both flies and humans shows that it has been relatively well conserved (functionally at least).
And given that we see similarities in the Pink1 gene and function between flies and humans, then perhaps we can apply what we see in flies to humans with regards to treatments.
Which brings us (finally!) to the research paper we wanted to look at today:
Title: Enhancing NAD+ salvage metabolism is neuroprotective in a PINK1 model of Parkinson’s disease<
Authors: Lehmann S, Loh SH, Martins LM.
Journal: Biol Open. 2016 Dec 23. pii: bio.022186.
PMID: 28011627 (this article is OPEN ACCESS if you would like to read it)
In this study, the researchers analysed Pink1 flies and found alterations in the activity of an enzyme called nicotinamide adenine dinucleotide (or NAD+). NAD+ is one of the major targets for the anti-aging crowd and there is some very interesting research being done on it (Click here for a good review on this). NAD+ is a coenzyme found in all living cells. A coenzyme functions by carrying electrons from one molecule to another (Click here for a nice animation that will explain this better). The researchers found that Pink1 mutant flies have decreased levels of NAD+.
The researchers were curious if a diet supplemented with the NAD+ would rescue the mitochondrial defects seen in the Pink1 mutant fly. Specifically, they fed the flies a diet high in the NAD+ precursor nicotinamide (being a precursor means that nicotinamide can be made into NAD+ once inside a cell). They found that not only did nicotinamide rescue the mitochondrial problems in the flies, but it also protected neurons from degeneration.
So why is the title of this post talking about Niacin and not nicotinamide?
Niacin (also known as vitamin B3 or nicotinic acid) – like nicotinamide – is also a precursor of NAD+. And in their discussion of the study, the researchers noted that a high level of dietary niacin has been associated with a reduced risk of developing Parkinson’s disease (Click here and here for more on this).
The researchers were quick to point out that while a high Niacin diet may be beneficial, it could not be considered a cure in anyway for people with Parkinson’s disease because although it may be able to slow the cell death it would not be able to replace the cells that have already been lost.
So what does it all mean?
Hang on a second. We’re not finished yet.
Numerous media outlets have made a big fuss about the Niacin diet angle to this research, and they have ignored another really interesting finding:
In their study the researchers mutated another gene in the Pink1 flies which also resulted in improved mitochondrial function and neuroprotection. That gene was Poly (ADP-ribose) polymerase (or PARP). Parp is an enzyme involved in DNA repair and cell division. It is produced in very high levels in many types of cancer and medication that inhibit or block Parp are being tested in the clinic as therapies in those cancers.
Interestingly, blocking Parp has been previously shown to be beneficial for cell survival in models of Parkinson’s disease (Click here and here for more information on this). So in addition to changing to a high niacin diet, it would be interesting to follow up this results as well.
Particularly for people with the Pink1 mutation.
And this is where the results of this study are particularly interesting: they may relate specifically to a small population within the Parkinson’s community – those with Pink1 mutations. It would be interesting to begin discussing and designing clinical studies that focus particularly on people in this population (similar to the Ambroxol study – click here for our post on this).
So what does it all mean? (again)
The results of the present study demonstrate two means by which people with a particular genetic mutation could be treated for Parkinson’s disease. Obviously further research is required, but the idea that we are approaching an age in Parkinson’s disease research where treatments could be personalised is very appealing. It will be interesting to see where all of this goes.
EDITOR’S NOTE: If nothing we have written here makes any sense, then maybe this video will help:
The banner for today’s post was sourced from Wallpapersinhq
It is with great frustration that we read today of the delayed start to the phase 2 clinical trial of the re-purposed cancer drug Nilotinib for Parkinson’s disease (click here for a story outlining the background, and click here for the Michael J Fox Foundation statement).
We have previously discussed both the preclinical and clinical research regarding Nilotinib and its use in Parkinson’s disease (click here and here for those posts). And the Parkinson’s community certainly got very excited about the findings of the small phase 1 unblinded clinical trial conducted by researchers at Georgetown University in 2015.
With the recent failure of the GDNF trial in Bristol, what the Parkinson’s community (both suffers and researchers alike) needs to do is refocus on moving ahead with exciting new projects, like Nilotinib. To hear that the follow-up trials for Nilotinib, however, will be delayed until 2017 (TWO YEARS after the initial results were announced) due to disagreements regarding the design of the study and who is seemingly in charge of the project, is both baffling and deeply disappointing.
Currently it appears that parties involved in the follow-up clinical trial have decided to go their separate ways, with the researchers at Georgetown University looking to conduct a single site phase 2 study of 75 subjects (if they can access the drug from supplier Novartis), while the Michael J Fox backed consortium will set up a multi-site phase 2 study.
We will continue to follow this situation as it develops and will report events as they happen.