Tagged: Mitochondria

NIX-ing the PARKIN and PINK1 problem

In American slang, to ‘nix‘ something is to ‘put an end to it’.

Curiously, a protein called NIX may be about to help us put an end to Parkinson’s disease, at least in people with specific genetic mutations.

In today’s post we will look at what NIX is, outline a new discovery about it, and discuss what this new information will mean for people living with Parkinson’s disease.


Sydney harbour. Source: uk.Sydney

Before we start, I would like the reader to appreciate that I am putting trans-Tasman rivalry side here to acknowledge some really interesting research that is being conducted in Australia at the moment.

And this is really interesting.

I have previously spoken a lot about mitochondria and Parkinson’s on this website. For the uninitiated, mitochondria are the power house of each cell. They help to keep the lights on. Without them, the party is over 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 tiny bean-shaped objects within the cell. They convert nutrients 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 (some cells have thousands) and highly organised within the cell, being moved around to wherever they are needed.

Like you and I and all other things in life, however, mitochondria have a use-by date.

As mitochondria get old and worn out (or damaged) with time, the cell will recycle them via a process called mitophagy (a blending of the words mitochondria and autophagy – the waste disposal system of each cell).

What does this have to do with Parkinson’s disease?

Well, about 10% of Parkinson’s cases are associated with particular genetic variations that render people vulnerable to developing the condition. Some of these mutations are in sections of DNA (called genes) that provide the instructions for proteins that are involved in the process of mitophagy. Two genes, in particular, are the focus of a lot of Parkinson’s-related research – they are called PARKIN and PINK1.

What do PARKIN and PINK1 do?

Continue reading

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QUATS going on?!?

BE WARNED: THIS POST MIGHT UPSET SOME READERS

A recently published research report has caused a bit of a fuss in the media, and I have been contacted by a lot of concerned readers regarding this particular study.

It deals with some chemicals – which can be found in everyday products – that may be having a negative effect on biological processes that are related to Parkinson’s disease – specifically, the normal functioning of the mitochondria (the power stations of each cell).

In today’s post we will discuss the new research, what the chemicals do, and whether the Parkinson’s community should be concerned.


Source: Sacramentodentistry

Toothpaste.

It is something that most of us take completely for granted in the modern world. A product that sits in our bathroom, by the sink or on a shelf, and 2-3 times per day we stick some of it in our mouth and brush it around a bit. Given the well ingrained habit of repetitively ingesting of the stuff, we have little trouble with the idea of switching brands or trying new variations (“Oooh look, this one will make your teeth whiter. Let’s try it”).

I mean, come on – it’s just toothpaste. It’s safe, right?

It probably won’t surprise many of you to learn that the composition of toothpaste has changed quite a bit over the years, but what might amaze you is just how many years are involved with that statement: 

Egyptian toothbrush. Source: Nathanpaarth

The Egyptians recognised the importance of looking after one’s teeth at a very early stage. Apparently they had a lot of trouble with their teeth because their bread had grit in it which wore away their enamel. As far back as 5000BC, they had a form of toothpaste that they used to clean their teeth. It was a mix of powdered ashes of ox hooves, myrrh, powdered and burnt eggshells, and pumice (Source: Wikipedia). The Greeks, followed by the Romans, improved on the recipes (by adding abrasive ingredients such as crushed bones and oyster shells – delightful, huh?), but it wasn’t until after World War I that the modern day pre-mixed toothpastes became popular.

The cavity fighting chemical, Fluoride, was first added to toothpastes in the 1890s, and in 1908 Newell Sill Jenkins (an American dentist) invented the first toothpaste that contained disinfectants. It was called Kolynos (from the Greek words Kolyo nosos (κωλύω νόσος), meaning “disease prevention”). 

Source: Flickr

Following the advent of Kolynos, most toothpaste companies added antiseptic and disinfectant agents to improve the quality and effectiveness of their product. Being offered a tooth cleaning product with magical antibiotic properties seemed to reassure consumers that they were buying something that might actually work. And this led to more and more chemicals being added to toothpaste. Such additions included chemical like triclosan, cetylpyridinium chloride and benzalkonium chloride.

These chemicals are safe though…right?

Continue reading

Mdivi-1: the small molecule that could?

Mitochondrial division inhibitor-1 (mdivi-1) is a small molecule drug that is demonstrating very impressive effects in preclinical models of Parkinson’s disease. With further research it could represent a potential future therapy for people with Parkinson’s disease, particularly those with genetic mutations affecting the mitochondria in their cells. 

What are mitochondria?

In this post, we will explain what mitochondria are, how they may be involved in Parkinson’s disease, and we will discuss what the results of new research mean for future therapeutic strategies.


 

Mitochondria are fascinating.

Utterly. Utterly. Fascinating.

On the most basic level, Mitochondria (mitochondrion, singular; from the Greek words mitos (thread) and chondros (granule)) are just tiny little bean-shaped structures within the cells in our body, and their primary function is to act as the power stations. They supply the bulk of energy that cells require to keep the lights on. This chemical form of energy produced by the mitochondria is called adenosine triphosphate (or ATP). Lots of mitochondria are required in each cell to help keep the cell alive (as is shown in the image below, which is showing just the mitochondria (red) and the nucleus (blue) of several cells).

Lots of mitochondria (red) inside cells (nucleus in blue). Source: Clonetech

That’s the basic stuff – the general definition you will find in most text books on biology.

But let me ask you this:

How on earth did mitochondria come to be inside each cell and playing such a fundamental role?

I don’t know. Are you going to tell me?

No.

Why not?

Because we simply don’t know.

But understand this: Mitochondria are intruders.

Continue reading

The autoimmunity of Parkinson’s disease?

Auto

In this post we discuss several recently published research reports suggesting that Parkinson’s disease may be an autoimmune condition. “Autoimmunity” occurs when the defence system of the body starts attacks the body itself.

This new research does not explain what causes of Parkinson’s disease, but it could explain why certain brain cells are being lost in some people with Parkinson’s disease. And such information could point us towards novel therapeutic strategies.


Nature_cover,_November_4,_1869

The first issue of Nature. Source: SimpleWikipedia

The journal Nature was first published on 4th November 1869, by Alexander MacMillan. It hoped to “provide cultivated readers with an accessible forum for reading about advances in scientific knowledge.” It has subsequently become one of the most prestigious scientific journals in the world, with an online readership of approximately 3 million unique readers per month (almost as much as we have here at the SoPD).

Each Wednesday afternoon, researchers around the world await the weekly outpouring of new research from Nature. And this week a research report was published in Nature that could be big for the world of Parkinson’s disease. Really big!

On the 21st June, this report was published:

Nature
Title: T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Authors: Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A
Journal: Nature. 2017 Jun 21. doi: 10.1038/nature22815.
PMID: 28636593

In their study, the investigators collected blood samples from 67 people with Parkinson’s disease and from 36 healthy patients (which were used as control samples). They then exposed the blood samples to fragments of proteins found in brain cells, including fragments of alpha synuclein – this is the protein that is so closely associated with Parkinson’s disease (it makes regular appearances on this blog).

What happened next was rather startling: the blood from the Parkinson’s patients had a strong reaction to two specific fragments of alpha synuclein, while the blood from the control subjects hardly reacted at all to these fragments.

In the image below, you will see the fragments listed along the bottom of the graph (protein fragments are labelled with combinations of alphabetical letters). The grey band on the plot indicates the two fragments that elicited a strong reaction from the blood cells – note the number of black dots (indicating PD samples) within the band, compared to the number of white dots (control samples). The numbers on the left side of the graph indicate the number of reacting cells per 100,000 blood cells.

Table1

Source: Nature

The investigators concluded from this experiment that these alpha synuclein fragments may be acting as antigenic epitopes, which would drive immune responses in people with Parkinson’s disease and they decided to investigate this further.

Continue reading

Oleuropein – “surely the richest gift of heaven?”

thomas-jefferson

The title of this post is a play on a Thomas Jefferson quote (“the olive tree is surely the richest gift of heaven“). Jefferson, the third President of the United States (1801 to 1809), was apparently quite the lover of food. During the Revolutionary War, while he was a U.S. envoy to France, Jefferson travelled the country. In Aix-en-Provence, he developed an admiration for olive trees, calling them “the most interesting plant in existence”.

Being huge food lovers ourselves, we here at the SoPD wholeheartedly agree with Jefferson. But we also think that olives are interesting for another reason:

They contain a chemical called Oleuropein.

In today’s post we’ll explore what is known about this chemical and discuss what it could mean for Parkinson’s disease.


olivve-pits

Olives. Source: Gardeningknowhow

The olive, also known by the botanical name ‘Olea europaea,’ is an evergreen tree that is native to the Mediterranean, Asia and Africa, but now found around the world. It has a rich history of economic and symbolic importance within western civilisation. And the fruit of the tree also tastes good, either by themselves or in a salad or pasta dish.

Traditional diets of people living around the Mediterranean sea are very rich in extra-virgin olive oil. Olives are an excellent source of ‘good’ fatty acids (monounsaturated and di-unsaturated), antioxidants and vitamins. Indeed, research has shown that the traditional Mediterranean diet reduces the risk of heart disease (Click here to read more on this).

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Olive oil. Source: Bonzonosvilla

There are also chemicals within the olive fruit that may have very positive benefits for Parkinson’s disease.

But before you rush out and gorge yourself on olives, we have one small piece of advice:

The chemical is called Oleuropein, and it is usually removed from olives due to its bitterness.

What is Oleuropein?

Oleuropein is a ‘phenylethanoid’ – a type of phenolic compound that is found in the leaf and the fruit of the olive. Phenolic compounds are produced by plants as a protective measure against different kinds of stress.

Oleuropein

Oleuropein. Source: Wikipedia

The main phenolic compounds found in olives are hydroxytyrosol and oleuropein – both of which give extra-virgin olive oil its bitter taste and both have demonstrated neuroprotective effects.

More research has been done on oleuropein so we will focus on it here (for more on hydroxytyrosol – please click here).

Oleuropein has been found to have many interesting properties, such as:

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The many properties of oleuropein. Source: Mdpi

What neuroprotective research has been done on Oleuropein?

Thus far, most of the research addressing this question has been conducted on models of Alzheimer’s disease. The first study

PLos1

Title: Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit.
Authors: Diomede L, Rigacci S, Romeo M, Stefani M, Salmona M.
Journal: PLoS One. 2013;8(3):e58893.
PMID: 23520540                 (This article is OPEN ACCESS if you would like to read it)

The Italian researchers who conducted this study treated a microscopic worm model of Alzheimer’s disease with oleuropein aglycone. We should not that oleuropein aglycone is a hydrolysis product of oleuropein (a hydrolysis product is a chemical compound that is broken apart by the addition of water). The microscopic worm used in the study are called Caenorhabditis elegans:

c_elegans

Caenorhabditis elegans – cute huh? Source: Nematode

Caenorhabditis elegans (or simply C. Elegans) are tiny creatures that are widely used in biology because they can be easily genetically manipulated and their nervous system is very simple and well mapped out (they have just 302 neurons and 56 glial cells!). The particular strain of C. elegans used in this first study produced enormous amounts 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 condition. A fragment of this protein (called Aβ42) begins clustering in the brains of people with Alzheimer’s disease. This clustering of Aβ42 goes on to form the plaques that are so characteristic of the Alzheimer’s affected brain.

The Italian researchers conducting this study had previously shown that oleuropein can inhibit the ability of Aβ42 to aggregate in cells growing in culture dishes (Click here to read more about that study), and they wanted to see if oleuropein had the same properties in actual live animals. So they chose the C. Elegans that had been genetically engineered to produce a lot of Aβ42 to test this idea.

In the C. Elegans that produce a lot of Aβ42 gradually become paralysed and their lives are shortened. By treating these worms with oleuropein, however, the Italian researchers found that there was less aggregation of Aβ42 (though the levels of the protein stayed the same), resulting in less plaque formation, and improved mobility (>50% reduction in paralysis) and survival compared to untreated Aβ42 producing C. Elegans.

Encouraged by this result, the researchers next moved on to studies in mice:

Plos2

Title: The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology.
Authors: Grossi C, Rigacci S, Ambrosini S, Ed Dami T, Luccarini I, Traini C, Failli P, Berti A, Casamenti F, Stefani M.
Journal: PLoS One. 2013 Aug 8;8(8):e71702.
PMID: 23951225                   (This article is OPEN ACCESS if you would like to read it)

For this study, the Italian researchers used the genetically engineered TgCRND8 mice. These mice have a mutant form of amyloid precursor protein (which, similar to Aβ42, is associated with Alzheimer’s disease). In the brains of these mice, amyloid clustering begins at 3 months of age, and dense plaques are evident from 5 months of age. The mice also exhibit a clear learning impairment from 3 months of age.

By treating these mice with oleuropein aglycone, the researchers observed a remarkable reduction in plaques in the brain, and those that were present appeared less compact and “fluffy” (their very technical description, not ours). In addition, there was a reduction in the activation of astrocytes and microglia (the helper cells in the brain), indicating a healthier environment.

These same researchers have observed the same results in a rat model of Alzheimer’s disease in a report published the next year (Click here to read more about this).

Interestingly, the oleuropein treated TgCRND8 mice also displayed a major increase in autophagy activity. As we discussed in our previous post (Click here to read that post), autophagy is the rubbish disposal/recycling system of each cell, and increasing the activity of this system can help to keep cells health (particularly if there is a lot of a genetically engineered protein present!).

The Italian researchers repeated this study, and published the results this year, with an interesting twist:

JCBP

Title: Oleuropein aglycone and polyphenols from olive mill waste water ameliorate cognitive deficits and neuropathology.
Authors: Pantano D, Luccarini I, Nardiello P, Servili M, Stefani M, Casamenti F.
Journal: Br J Clin Pharmacol. 2017 Jan;83(1):54-62.
PMID: 27131215

In this study, the researchers tested the same genetically engineered mice, but with two different treatments:

  1.  Two much lower doses of oleuropein (4 and 100 times lower)
  2.  A mixture of polyphenols from olive mill concentrated waste water

The lowest dose of oleuropein (100 times less oleuropein than the previous study) did not provide any significant improvements for the mice, but the intermediate dose (only 4 times less oleuropein than the previous study) did provide significant benefits. These result indicate that there is a dose-dependent range to the beneficial properties of oleuropein.

The researchers also observed very similar beneficial effects from the mice drinking a mixture of polyphenols from olive mill concentrated waste water. Given these results, the investigators are now seeking to design appropriate conditions to perform a clinical trial to assess better the possible use of oleuropein (or a mix of olive polyphenols) against Alzheimer’s disease.

Ok, but what research has been done with oleuropein and Parkinson’s disease?

Unfortunately, not much.

A research group in Iran has looked at the effect of oleuropein in aged rodents and found an interesting result:

Iran
Title: Antioxidant role of oleuropein on midbrain and dopaminergic neurons of substantia nigra in aged rats.
Authors: Sarbishegi M, Mehraein F, Soleimani M.
Journal: Iran Biomed J. 2014;18(1):16-22.
PMID: 24375158                 (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators took twenty aged rats (18-month-old) and randomly assigned them to two groups: a treatment group (which received a daily dose of 50 mg/kg of oleuropein for 6 months) and a control group (which received just water). Following these treatments, the investigators found an increase in the activity of anti-oxidant agents (such as superoxide dismutase, catalase and glutathione) in the treatment group compared to control group. The treated rats also had significantly more dopamine neurons in the region of the brain affected by Parkinson’s disease (the substantia nigra). The investigators concluded that oleuropein consumption in a daily diet may be useful in reducing oxidative stress damage by increasing the antioxidant activity in the brain.

This first study was followed more recently by a report from a group in Quebec (Canada) who investigated oleuropein use in a cell culture model of Parkinson’s disease:

Oleu
Title: Oleuropein Prevents Neuronal Death, Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in a Dopaminergic Cellular Model.
Authors: Achour I, Arel-Dubeau AM, Renaud J, Legrand M, Attard E, Germain M, Martinoli MG.
Journal: Int J Mol Sci. 2016 Aug 9;17(8).
PMID: 27517912              (This article is OPEN ACCESS if you would like to read it)

The researcher conducting this study wanted to determine if oleuropein could prevent neuronal degeneration in a cellular model of Parkinson’s disease. They exposed cells to the neurotoxin 6-hydroxydopamine (6-OHDA) and then investigated mitochondrial oxidative stress and autophagy.

What is mitochondrial oxidative stress?

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

Oxidative stress results from too much oxidation. Oxidation is the loss of electrons from a molecule, which in turn destabilises the molecule. Think of iron rusting. Rust is the oxidation of iron – in the presence of oxygen and water, iron molecules will lose electrons over time. Given enough time, this results in the complete break down of objects made of iron.

1112dp_01rust_bustingrusty_bottom_of_door

Rust, the oxidation of metal. Source: TravelwithKevinandRuth

The exact same thing happens in biology. Molecules in your body go through a similar process of oxidation – losing electrons and becoming unstable. This chemical reaction leads to the production of what we call free radicals, which can then go on to damage cells. A free radical is an unstable molecule – unstable because they are missing electrons.

imgres

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.

Now if this oxidative process starts in the mitochondria, it can be very bad for a cell.

And what is autophagy?

Yes, the researchers also looked at autophagy levels in their cells. Autophagy is an absolutely essential function in a cell. 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.

Think of autophagy as the waste disposal/recycling process of the cell.

Print

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.

Ok, so what did the researchers find?

Well, by pretreating the their cells with oleuropein 3 hours before exposing them to the neurotoxin, the investigators found a significant neuroprotective effect. There was a significant reduction in mitochondrial production of free radicals, and the investigators found an important role for oleuropein in the regulation of autophagy.

And the good news is that other research groups have observed similar beneficial effects of oleuropein in cell culture models of Parkinson’s disease (Click here to read more about that).

The bad news is: that is all the published research on oleuropein and Parkinson’s disease we could find (and we would be happy to be corrected on this if people are aware of other reports!).

So what does Oleuropein do in the brain?

This is a good question, but with so little research done in this area, it is hard to answer.

We know that oleuropein is well absorbed by the human body and that it is relatively stable (Click here to read more on this). In addition, it can cross the blood-brain-barrier – in rodents at least (Click here to read more on that).

Obviously (based on the research we described above), we know that oleuropein has anti-oxidant promoting activities. In addition, it appears to be doing something with regards to autophagy. And it may be regulating autophagy by acting as an inhibitor of mammalian target of rapamycin (mTOR) activation.

What is mTOR?

mTOR is a protein that binds with other proteins to form the nexus of a signalling pathway which integrates both intracellular and extracellular signals (such asnutrients, growth factors, and cellular energy status) and then serves as one of the central instructors of how the cell should respond.

For example, insulin can signal to mTOR the status of glucose levels in the body. mTOR also deals with infectious or cellular stress-causing agents, thus it could be involved in a cells response to conditions like Parkinson’s disease.

ncb2763-f11

Factors that activate mTOR. Source: Selfhacked

One important property of mTOR is its ability to block autophagy (the recycling process of the cell that we discussed above). Recently, the Italian researchers whose work we reviewed above, found that oleuropein can activate autophagy by blocking the mTOR pathway:

Onco

Title: Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight.
Authors: Rigacci S, Miceli C, Nediani C, Berti A, Cascella R, Pantano D, Nardiello P, Luccarini I, Casamenti F, Stefani M.
Journal: Oncotarget. 2015 Nov 3;6(34):35344-57.
PMID: 26474288                (This article is OPEN ACCESS if you would like to read it)

The researchers conducting this study found that treatment with oleuropein caused an increase in autophagy in both cell culture and in a mouse model of Alzheimer’s disease, and they demonstrated that it achieved this by blocking the mTOR pathway.

Has anyone ever looked at oleuropein in the clinic?

No, not to our knowledge (and we are happy to be corrected on this).

There have been six clinical trials of olive leaf extract (the majority of which is oleuropien), but none of them have been focused on any neurological conditions.

 

So oleuropein is safe then?

It is a widely available supplement that a lot of people use to help lower bad cholesterol and blood pressure, so yes it can be considered safe. But any decision to experiment with oleuropein should only be made in consultation with your regular medically trained physician.

Why? Because there are always caveats.

Importantly, individuals with low blood pressure and diabetes may suffer even lower blood pressure and blood glucose levels as a result of consumption of oleuropein. Oleuropein may also interact with other pharmaceutical drugs that are designed to lower blood pressure or regulate diabetes. Such interactions could be dangerous.

And this is a particularly important factor for Parkinson’s disease as up to 30% of people with Parkinson’s may be glucose intolerant (Click here to see our post on Parkinson’s & diabetes).

Those who experience symptoms such as headache, nausea, flu-like symptoms, fainting, dizziness, and other life threatening symptoms should medical attention immediately.

What does it all mean?

We are grateful to regular reader (Don) who brought oleuropein to our attention. It is a very interesting chemical and we are definitely intrigued by it. We would certainly like to see more research on oleuropein in models of Parkinson’s disease.

Attentive readers will have noticed that most of the research discussed above have been conducted in the last 5-10 years. This suggests that oleuropein research is still in its infancy, particularly with regards to research on neurological conditions. And we hope that by reporting on it here, we will be bringing it to the attention of researchers.

Oleuropein is extracted from all parts of the olive tree (the leaves, bark, root, and fruit). It forms part of the defence system of the olive tree against stress or infection. Perhaps we could apply some of its interesting properties to Parkinson’s disease.


EDITORIAL NOTE:  Under absolutely no circumstances should anyone reading the material on this website consider it medical advice. The information 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 and supplements 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 this post was sourced from jrbenjamin

Sheffield: flies, fish and a Tigar

total-produce-ltd-sheffield1

When people in England think of the city of Sheffield, quite often images of a great industrial past will come to mind.

They usually don’t think of the flies, fish and (yes) a Tigar (no, not a typo!) that are influencing Parkinson’s disease research in the city.

In today’s post we will look at how the re-invention of a city could have a major impact on Parkinson’s disease.


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The industrial heritage of Sheffield. Source: SIMT

It is no under statement to say that the history of Sheffield – a city in South Yorkshire, England –  is forged in steel.

In his 1724 book, “A tour thro’ the whole island of Great Britain, the author Daniel Defoe wrote of Sheffield:

“Here they make all sorts of cutlery-ware, but especially that of edged-tools, knives, razors, axes, &. and nails; and here the only mill of the sort, which was in use in England for some time was set up, for turning their grindstones, though now ’tis grown more common”

Sheffield has a long history of metal work, thanks largely to its geology: The city is surrounded by fast-flowing rivers and hills containing many of the essential raw materials such as coal and iron ore.

And given this fortunate circumstance and an industrious culture, the city of Sheffield particularly prospered during the industrial revolution of the mid-late 1800s (as is evident from the population growth during that period).

sheffpop

The population of Sheffield over time. Source: Wikipedia

But traditional manufacturing in Sheffield (along with many other areas in the UK) declined during the 20th century and the city has been forced to re-invent itself in the early 21st century. And this time, rather than taking advantage of their physical assets, the city is focusing on its mental resources.

Great. Interesting stuff. Really. But what does this have to do with flies, fish and Parkinson’s disease???

Indeed. Let’s get down to business.

sitran_sunrise_785px

The Sheffield Institute for Translational Neuroscience (SITraN) was officially opened in 2010 by Her Majesty The Queen. It is the first European Institute purpose-built and dedicated to basic and clinical research into Motor Neuron Disease as well as related neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease.

Since its opening, the institute has published some pretty impressive research, particularly in the field of Parkinson’s disease.

And here is where we get to the flies:

pink_fly-1410843

Pink flies. Source: Wallpapersinhq

We have previously discussed “Pink” flies and their critical role in Parkinson’s research (Click here to read that post).

Today we are going to talk about Lrrk2 flies.

What is Lrrk2?

This is Sergey Brin.

sergey_brin

He’s a dude.

One of the founders of the search engine company “Google”. Having changed the world, he is now turning his attention to other projects.

One of those other projects is close to our hearts: Parkinson’s disease.

In 1996, Sergey’s mother started experiencing numbness in her hands. Initially it was believed to be RSI (Repetitive strain injury). But then her left leg started to drag. In 1999, following a series of tests, Sergey’s mother was diagnosed with Parkinson’s disease. It was not the first time the family had been affected by the condition: Sergey’s late aunt had also had Parkinson’s disease.

Both Sergey and his mother have had their DNA scanned for mutations that increase the risk of Parkinson’s disease. And they discovered that they were both carrying a mutation on the 12th chromosome, in a gene called PARK8 – one of the Parkinson’s disease associated genes. Autosomal dominant mutations (meaning if you have just one copy of the mutated gene) in the PARK8 gene dramatically increase one’s risk of developing Parkinson’s disease.

PARK8 provides the instructions for making an enzyme called Leucine-rich repeat kinase 2 (or Lrrk2).

Protein_LRRK2_PDB_2ZEJ

The structure of Lrrk2. Source: Wikipedia

Also known as ‘Dardarin (from the Basque word “dardara” which means trembling), Lrrk2 has many functions within a cell – from helping to move things around inside the cell to helping to keep the power on (involved with mitochondrial function).

Fig-2-LRRK2-involvement-in-cellular-mechanisms-Several-data-posit-that-LRRK2-through

Source: Researchgate

NOTE: Curiously, mutations in the PARK8 gene are also associated with Crohn’s disease (Click here and here for more on this) – though the mutation is in a different location for PD.

Now, not everyone with this particular mutation will go on to develop Parkinson’s disease, and Sergey has decided that his chances are 50:50. But he does not appear to be taking any chances though. Being one of the founders of a large company like Google, has left Sergey with considerable resources at his disposal. And he has chosen to focus some of those resources on Lrrk2 research (call it an insurance  policy). He has done this via considerable donations to groups like the Michael J Fox foundation.

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Actor Michael J Fox was diagnosed at age 30. Source: MJFox foundation

So just as Pink flies derive their name from mutations in the Parkinson’s associated Pink1 gene, Lrrk2 flies have mutations in the Lrrk2 gene.

So what have the researchers at Sheffield done with the Lrrk2 flies?

In 2013, the Sheffield researchers published an interesting research report:

brain

Title: Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson’s disease
Authors: Mortiboys H, Aasly J, Bandmann O.
Journal: Brain. 2013 Oct;136(Pt 10):3038-50.
PMID: 24000005

In this study, the investigators took 2000 drugs (including 1040 licensed drugs and 580 naturally occurring compounds) and conducted a massive screen to identify drugs that could rescue mitochondrial dysfunction in PARK2 (Pink1) mutant cells.

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

In certain genetic forms of Parkinson’s disease (such as those associated with mutations in the PARK2 gene), the mitochondria in cells becomes dysfunctional and may not be disposed of properly (Click here to read our previous post related to this).

In their huge screen of 2000 drugs, the researchers in Sheffield identified 15 drugs that could rescue the mitochondria dysfunction in the PARK2 skins cells. Of those 15 compounds, two were chosen for further functional studies. They were:

  • Ursocholanic acid
  • Dehydro(11,12)ursolic acid lactone

Neither ursocholanic acid nor dehydro(11,12)ursolic acid lactone are FDA-licensed drugs. We have little if any information regarding their use in humans. Given this situation, the researchers turned their attention to the chemically related bile acid ‘ursodeoxycholic acid’, which has been in clinical use for more than 30 years.

What is Ursodeoxycholic Acid?

Ursodeoxycholic Acid (or UDCA) is a drug that is used to to improve bile flow and reduce gallstone formation. In the USA it is also known as ‘ursodiol’.

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Ursodiol. Source: Wikimedia

Bile is a fluid that is made and released by your liver, and it stored in the gallbladder. Its function is to help us with digestion. UDCA occurs naturally in bile – it is basically a bile acid and can therefore be useful in dissolving gallstones. UDCA has been licensed for the treatment of patients since 1980. UDCA also reduces cholesterol absorption.

So what did the Sheffield researchers find with UDCA?

The researchers tested UDCA on mitochondrial function in PARK2 skin cells, and they found that the drug rescued the cells. They then tested UDCA on skin cells from people with Parkinson’s disease who had mutations in the PARK8 (Lrrk2) gene (G2019S).

The researchers had previously found impaired mitochondrial function and morphology in skin cells taken from people with PARK8 associated Parkinson’s disease (Click here to read more about this), and other groups had reported similar findings (Click here for more on this).

And when they treated the Lrrk2 cells with UDCA, guess what happened?

UDCA was able to rescue the mitochondrial effect in those cells as well!

Obviously these results excited the Sheffield scientists and they set up a collaboration with researchers at York University and from Norway, to look at the potential of UDCA in rescuing the fate of Lrrk2 flies. The results of that study were published two years ago:

Oliver

Title: UDCA exerts beneficial effect on mitochondrial dysfunction in Lrrk2 (G2019S) carriers and in vivo.
Authors: Mortiboys H, Furmston R, Bronstad G, Aasly J, Elliott C, Bandmann O.
Journal: Neurology. 2015 Sep 8;85(10):846-52.
PMID: 26253449        (This article is OPEN ACCESS if you would like to read it).

The researchers tested UDCA on flies (or drosophila) with specific Lrrk2 mutations (G2019S) display a progressive loss of photoreceptor cell function in their eyes. The mitochondria in the photoreceptor are swollen and disorganised. When the investigators treated the flies with UDCA, they found approximately 70% rescue of the photoreceptor cells function.

The researchers in Sheffield concluded that UDCA has a marked rescue effect on cells from a Parkinson’s disease-associated gene mutation model, and they proposed that “mitochondrial rescue agents may be a promising novel strategy for disease-modifying therapy in Lrrk2-related PD, either given alone or in combination with Lrrk2 kinase inhibitors” (for more information about the Lrrk2 inhibitors they refer, click here).

And the good news regarding this line of research: other research groups have also observed similar beneficial effects with UDCA in models of Parkinson’s disease:

Low1

Title: Ursodeoxycholic acid suppresses mitochondria-dependent programmed cell death induced by sodium nitroprusside in SH-SY5Y cells.
Authors: Chun HS, Low WC.
Journal: Toxicology. 2012 Feb 26;292(2-3):105-12.
PMID: 22178905

This research group also demonstrated that UDCA could reduce cell death in a cellular model of Parkinson’s disease.

And this study was followed by another one from a different research group, which involved testing UDCA in animals:

Salem1

Title: Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations.
Authors: Abdelkader NF, Safar MM, Salem HA.
Title: Mol Neurobiol. 2016 Mar;53(2):810-7.
PMID: 25502462

These researchers found UDCA rescued a rodent model of Parkinson’s disease (involving the neurotoxin rotenone). UDCA not only improved mitochondrial performance in the rats, but also demonstrated anti-inflammatory and anti-cell death properties.

Given all this research, the Sheffield researchers are now keen to test UDCA in clinical trials for Parkinson’s disease.

Has anyone tested UDCA in the clinic for Parkinson’s disease?

Not that we are aware of, but two groups are interested in attempting it.

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Firstly, the University of Minnesota – Clinical and Translational Science Institute has registered a trial (Click here to read more about this). This trial will not, however, be testing efficacy of the drug on Parkinson’s symptoms. It will focus on measuring UDCA levels in individuals after four weeks of repeated high doses of oral UDCA (50mg/kg/day), and determining the bioenergetic profile and ATPase activity in those participants. Basically, they want to see if UDCA is safe and active in people with Parkinson’s disease.

The CurePD trust (in the UK) is also currently seeking to run a clinical trial for UDCA (Click here for more on this). The group are currently organising the funding for that trial.

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EDITOR’S NOTE HERE: Before we move on, the team at the SoPD would like to say that while UDCA is a clinically available drug, it is still experimental for Parkinson’s disease. There is no indication yet that it has beneficial effects in people with Parkinson’s disease. In addition, UDCA is also is known to have side effects, which include flu symptoms, nausea, diarrhea, and back pain. And individuals have been known to have allergic reactions to UDCA treatment (Click here and here for more on the side effects of UDCA). Thus we must impress caution on anyone planning to experiment with this drug. Before attempting any kind of change in a current treatment regime, PLEASE discuss your plans with a medically qualified physician who is familiar with your case history.


Ok, so that was the flies research, what about the fish? And the… uh, tigar?

Yes. The fish are called Zebrafish (or Danio rerio).

They are a tropical freshwater fish that is widely used in biological research.

Zebrafisch

Biology researchers love these little guys because their genome has been fully sequenced and they has well characterised and testable behaviours. In addition, their development is very rapid (3 months), and its embryos are large and transparent.

And the researchers at Sheffield are using these fish to study Parkinson’s disease.

How did they do that?

tiger

Title: TigarB causes mitochondrial dysfunction and neuronal loss in Pink1 deficiency
Authors: Flinn LJ, Keatinge M, Bretaud S, Mortiboys H, Matsui H, De Felice E, Woodroof HI, Brown L, McTighe A, Soellner R, Allen CE, Heath PR, Milo M, Muqit MM, Reichert AS, Köster RW, Ingham PW, Bandmann O.
Journal: Ann Neurol. 2013 Dec;74(6):837-47.
PMID:
24027110        (This article is OPEN ACCESS if you would like to read it)

Firstly, the group at Sheffield generated zebrafish that had a mutation in the Parkinson’s associated gene ‘PARK6’. This gene provides the plans for the production of a protein called Pink1 (we have previously discussed Pink1 – click here to read more on this).

In normal healthy cells, the Pink1 protein is absorbed by mitochondria and eventually degraded as it is not used. In unhealthy cells, however, this process becomes inhibited and Pink1 starts to accumulate on the outer surface of the mitochondria. Sitting on the surface, it starts grabbing another Parkinson’s associated protein called Parkin. This pairing is a signal to the cell that this particular mitochondria is not healthy and needs to be removed.

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Pink1 and Parkin in normal (right) and unhealthy (left) situations. Source: Hindawi

The process by which mitochondria are removed is called mitophagy. Mitophagy is part of the autophagy process, which is an absolutely essential function in a cell. 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.

Think of autophagy as the waste disposal/recycling process of the cell.

Print

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.

In the case of a PARK6 mutations, Pink1 protein can not function properly with Parkin and the autophagy process breaks down. As a result, the old or unhealthy mitochondria start to pile up in the cell, resulting in the cell getting sick and dying.

Now back to the Zebrafish.

When the Sheffield researchers mutated PARK6 in the zebrafish, they noticed that the fish had a very early and persistent loss of dopamine neurons in their brains. These fish also had enlarged, unhealthy mitochondria and reduced mitochondrial activity.

Given this result, the investigators next wanted to identify which genes have increased or decreased levels of activity as a result of this genetic manipulation. They identified 108 genes that were higher in the PARK6 mutant, and 146 genes had lower activity.

One gene in particular had activity levels 12 times higher in the PARK6 mutant fish than the normal zebrafish.

The name of that gene? TP53-Induced Glycolysis And Apoptosis Regulator (or Tigar).

What is Tigar?

Tigar is a gene that provides the instructions for making a protein that is activated by p53 (also known as TP53).

What does that mean?

p53 is a protein that has three major functions: controlling cell division, DNA repair, and apoptosis (or cell death). p53 performs these functions as a transcriptional activator (that is a protein that binds to DNA and helps produce RNA (the process of transcription) – see our previous post explaining this).

800px-P53

p53 protein structure, bound to DNA (in gold). Source: Wikipedia

In regulating the cell division, p53 prevents cells from dividing too much and in this role it is known as a tumour suppression – it suppresses the emergence of cancerous tumours. Genetic mutations in the p53 gene result in run away cell division, and (surprise!) as many as 50% of all human tumours contain mutations in the p53 gene.

Apop

Cancer vs no cancer. Source: Khan Academy

In DNA repair, p53 is sometimes called “the guardian of the genome” as it prevents mutations and helps to conserve stability in the genome. This function also serves to prevent the development of cancer, by helping to repair potentially cancer causing mutations….and in this role it is known as a tumour suppression. Obviously, if there is a mutation in the p53 gene, less DNA repair will occur – increasing the risk of cancer occurring.

And finally, in cell death, p53 plays a critical role in telling a cell when to die. And (continuing with the cancer theme), if there is a mutation in the p53 gene, fewer cells will be told to die – increasing the risk of cancer occurring. And in this role p53 is known as a tumour suppression.

In normal cells, the levels of p53 protein are usually low. When a cell suffers DNA damage and stress, there is often an increase in the amount of p53 protein. If this increases past a particular threshold, then the cell will be instructed to die.

If you haven’t guessed yet, p53 is a major player inside most cell, and it controls the activity of a lot of genes.

And one of those genes is Tigar.

But what does Tigar actually do?

So we have explained the “TP53-Induced” part of the “TP53-Induced Glycolysis And Apoptosis Regulator” name, let’s now focus on the “Glycolysis And Apoptosis Regulator”

Tigar is an interesting protein because it is an enzyme that primarily functions as a regulator of the breaking down of glucose (“Glycolysis” involves the conversion of glucose into a chemical called pyruvate). In addition to this role, however, Tigar acts in preventing cell death (or apoptosis).

Increased levels of Tigar protects cells from oxidative-stress induced apoptosis, by decreasing the levels of free radicals. In this way, it promotes anti-oxidant activities.

But hang on a second, anti-oxidant activity should be good for the cell right? Why are the dopamine cells are dying if Tigar levels are increasing in the PARK6 mutants?

Fantastic question!

The answer: TIGAR is also a negative regulator of a process called mitophagy. As we discussed above, mitophagy is the process of removing mitochondria by autophagy. Increases in the levels of TIGAR blocks mitophagy in a cell, and results in an increased number of swollen and unhealthy mitochondria in those cells (Click here to read more about this). These swollen mitochondria are comparable to the enlarged mitochondria identified the PARK6 zebrafish by the Sheffield researchers.

And the researchers believe that this may be the cause of the cell death in the PARK6 zebrafish – the double impact of PARK6 and Tigar induced problems with mitophagy.

NOTE: Problems with mitophagy is believed to be an important mechanism in the development of early-onset Parkinson’s disease (Click here for a recent review on this)

Ok, and what did the Sheffield researchers do next?

Given that there was such a huge increase in Tigar levels in the PARK6 zebrafish, the investigators decided to reduce Tigar levels in the PARK6 zebrafish to see what impact this would have on the fish (and their mitochondria).

Remarkably, reductions of Tigar levels resulted in complete rescue of the dopamine neurons in the PARK6 fish. It also increased mitochondrial activity in those cells, and reduced the activation of the microglia cells, which can also play a role in the removal of sick cells in the brain.

The researchers concluded that the results demonstrate that TIGAR is “a promising novel target for disease‐modifying therapy in Pink1‐related Parkinson’s disease”.

And what are the researchers planning to do next with Tigar?

Prof Oliver Bandmann, the senior scientist who ran the study, has said that they “need to finish studying TIGAR levels in the brains of people with Parkinson’s and want to better understand how this protein is involved in maintaining the cell batteries – called ‘mitochondria'” (Source).

Our guess is that the group will also be conducting studies looking at Tigar reduction in rodent models of Parkinson’s disease to determine if this is a viable target in mammals. If Tigar reduction in rodents is found to be effective, the researchers will probably turn their attention to drug screening studies to identify currently available drugs that can reduce the activity of Tigar. Such a drug would provide us with yet another potential treatment for Parkinson’s disease.

We’ll be keeping an eye out for these pieces of research.

This is all very interesting. What does the future hold for Parkinson’s research in Sheffield?

Well, in a word: Keapstone.

Que?

In March, the University of Sheffield and Parkinson’s UK have launched a new £1 million virtual biotech company called “Keapstone Therapeutics” (see the press release by clicking here).

parkinsons_virtual_biotech_graphic

Source: Parkinson’s UK

The goal of the company – the first of its kind – is to combine world-leading research from the University with funding and expertise from the charity to help develop revolutionary drugs for Parkinson’s disease.

What is virtual about it? The biotech won’t be building its own labs, employing a team of specialist laboratory scientists, or buying any high-tech equipment (which would all be incredibly expensive). Rather they will form partnerships with groups that do specific tasks the best.

Here is a video of Dr Author Roach (director of Research at Parkinson’s UK) explaining the idea behind this endeavour:

By seeking a collaboration with Sheffield in the creation of a spin-out biotech company, Parkinson’s UK is not only acknowledging Sheffield’s track record, but also making an investment in their future research. While we cannot be entirely sure of what the long-term future holds for Parkinson’s research in Sheffield, we do know that Keapstone will be an important aspect of it in the immediate future.

Could this be a model for the future of Parkinson’s disease research? Only time will tell. We will have a closer look at Keapstone Therapeutics in an upcoming post.

Click here to learn more about the virtual biotech project.

So what does it all mean?

In 2017, we here at the SoPD have decided to begin highlighting some of the Parkinson’s disease research centres as an addition feature on the blog. We have not been approached by the research group in Sheffield or the University itself, and our selection of this city as our first case study was based purely on the fact that we really like what is happening there with regards to Parkinson’s research!

The research group in Sheffield has undertaken multiple lines of research which could potentially providing us with several novel treatment options for Parkinson’s disease. These lines of research have focused not only on clinically available drugs, but also identifying novel targets. We like what they are doing and will keep a close eye on progress there.

And over the next year we will select additional centres of Parkinson’s research based on the same criteria (us liking what they are doing). Our next case study will be the Van Andel Research Institute in Grand Rapids, Michigan (we would hate to be accused of having a UK bias).


EDITORIAL NOTE:  Under absolutely no circumstances should anyone reading the material on this website consider it medical advice. The information 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 TotalProduceLocal

Resveratrol: From the folks who brought you Nilotinib

 

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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 herehere 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:

trial.jpg

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?

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.

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

Pink flies in Leicester at it again

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Imagine discovering a protein that could make the power supply of your cells healthier AND perhaps provide a new therapeutic target for Parkinson’s disease.

That would be a pretty big deal right?

Well, this week, researchers may have found just such a protein. In today’s post we will review their finding and discuss what it means for Parkinson’s disease.


This is Dr Miguel Martins:

miguel_martins

Source: Tox.mrc.ac.uk

He’s a dude.

Dr Martins is a group leader at the MRC toxicology unit in Leicester – a city in the East Midlands of England.

leicester-town-hall-squareLeicester. Source: Keithvazmp

You may have heard of Leicester. Last year their football team had a dream season, miraculously winning the Premier league title despite starting with odds of 5000:1.

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Last season’s winners. Source: Goal.com

This season, however,….well, uh…

Let’s move on, shall we.

Recently we reviewed Dr Martins research group’s work on ‘Pink flies’ and how they survive longer on Niacin rich diets (Click here for that post). He and his group were again publishing research this week, involving new a new study highlighting a protein that may help with keeping mitochondria healthy.

What are mitochondria?

Good question.

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.

So what has Dr Martins group found?

This week they published this study:

atf4

Title: dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective.
Authors: Celardo I, Lehmann S, Costa AC, Loh SH, Miguel Martins L.
Journal: Cell Death Differ. 2017 Feb 17. [Epub ahead of print]
PMID: 28211874       (This article is OPEN ACCESS if you would like to read it)

In the study, the researchers were interested in determining what changes occur in the flies that are missing the Parkinson’s disease associated genes PINK1 or PARKIN, particularly which transcription factors are affected.

What is a transcription factor?

Another good question.

Ok, so you remember your high school science class when the adult at the front of the class was explaining biology 101? And they were saying that DNA gives rise to RNA, RNA gives rise to protein? The central dogma of biology. Remember this?

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The basic of biology. Source: Youtube

Ultimately this DNA-RNA-Protein mechanism is a circular cycle, because the protein that is produced using RNA is required at all levels of this process. Some of the protein is required for making RNA from DNA, while other proteins are required for making protein from the RNA instructions.

A transcription factor is a protein that is involved in the process of converting (or transcribing) DNA into RNA.

Importantly, a transcription factor can be an ‘activator’ of transcription – that is initiating or helping the process of generating RNA from DNA.

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An example of a transcriptional activator. Source: Khan Academy

Or it can be a repressor of transcription – blocking the machinery (required for generating RNA) from doing it’s work.

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An example of a transcriptional repressor. Source: Khan Academy

In their study, Dr Martins and colleagues were looking for changes in the levels of proteins that either initiate or repress transcription, as these are the proteins that are ultimately at the start of the process of making things happen.

And what do Parkin and Pink1 actually do?

About 10% of cases of Parkinson’s disease can be attributed to genetic mutations in particular genes. PINK1 and PARKIN are two of those genes.

People with particular mutations in the PINK1 or PARKIN gene are vulnerable to developing an early onset form of Parkinson’s disease.

As to what the protein that is generated from PINK1 or PARKIN DNA & RNA, well in normal, healthy cells, the PINK1 protein 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.

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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.

In the absence of PINK1 and PARKIN – as is the case in some people with Parkinson’s disease who have genetic mutations in these genes – we believe that sick/damaged mitochondria start to pile up and are not disposed of appropriately. This results in the cell dying.

Ok, so the researchers were looking for transcription factors that change in the absence of PINK1 and PARKIN. How did they do this experiment?

They used flies.

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PINK flies. Source: Wallpapersinhq

The researchers took the heads (yes, I know, delightful stuff) of ‘young’ 3-day-old Pink1 and Parkin mutant flies and compared them to ‘aged’ heads from 21- and 30-day-old Parkin and Pink1 mutant flies, respectively. The comparison was specifically looking at transcription factors that change over time.

This analysis revealed a protein called activating transcription factor 4 (or ATF4).

The researchers found that ATF4 levels were higher in both Pink1 and Parkin mutants than levels in control flies. Importantly, the researchers next looked at the genes that this transcription factor (ATF4) was regulating, and they found that ATF4 was encouraging the production of proteins that protect mitochondria. The researchers noticed that when they reduced ATF4 in flies, the levels of these critical mitochondrial proteins dropped as well.

When the researchers reduced the levels of each of these critical mitochondrial proteins in flies, it resulted in impaired climbing ability (suggesting a locomotor deficit) and decreased lifespan. Interestingly, these protective mitochondrial proteins are increased in the Pink1 and Parkin flies, suggesting that efforts to keep the mitochondria healthy are active inside the cells.

Finally, the researchers increased the levels of these protective mitochondrial proteins in the Pink1 and Parkin mutants and they found that the mitochondrial function was improved, and neuronal cell loss was avoided. They concluded that their findings demonstrate a central role for ATF4 signalling in Parkinson’s disease and that this protein may represent a target for new therapeutic strategy.

So what does it all mean?

The researchers behind this study were looking for biological pathways that are altered in genetic forms of Parkinson’s disease and they have identified a protein that is involved with keeping mitochondria healthy. This pathway could represent a new therapeutic target for future treatments, and also opens a new door in our understanding of Parkinson’s disease.

ATF4 is currently not directly targeted by any medications (that we are aware of), but there are drugs in clinical trials that target proteins that subsequently activate ATF4. For example, Oncoceutics Inc. have a drug candidate called ONC201 (currently in phase II trials for brain cancer) which kills solid tumor cells by triggering an stress response which is dependent on ATF4 activation.

moa-diagram-5-31-16

Source: Oncoceutics Inc

We are not for a second suggesting that this is a viable drug for Parkinson’s disease (so PLEASE DON’T rush out and besiege the company for all of their stocks!) – ATF4 should be considered a very experimental target until these results are replicated by independent research groups. We are mentioning ONC201 here simply to indicate that there is a field of research surrounding this potential target (ATF4) and it may be worthwhile for the Parkinson’s community to follow up this line of investigation.

We are assuming that while Leicester football club is struggling, the Martins lab are currently investigating compounds that activate ATF4 (and the other critical mitochondrial proteins), and we will report any follow up work as it comes to hand.

Watch this space.


And if nothing we’ve written here makes any sense, the good folks at Leicester University have kindly provided a short video explaining the research:


Postscript (March 2017):

matters_journal

The Martins lab have done it again!

This time in the OPEN ACCESS online journal Science Matters, they have published this article:

Matters

Title: Folinic acid is neuroprotective in a fly model of Parkinson’s disease associated with pink1 mutations
Authors: Lehmann S , Jardine J, Garrido – Maraver J, Loh SH, & Martins LM
Journal: Science Matters

In this study, the researchers demonstrated that a folinic acid-enriched diet might delay or prevent the neuronal loss in people with PINK1 associated Parkinson’s disease. They present data suggesting that beginning an intake of Folinic acid in early to middle stages of adulthood prevents the degeneration of dopamine neurons in pink1 mutant flies.

Folinic acid (also known as leucovorin) is a medication used to decrease the toxic effects of chemotherapy drugs. The pharmacokinetics of leucovorin suggests that it readily crosses the blood-brain-barrier (Source), so it would be possible for a clinical trial to be set up in human. Before taking that path, however, more testing is required (ideally in a mammalian model of Parkinson’s disease).

Amazing that all these results are coming from silly old flies though, huh?


The banner for today’s post was sourced from Tox.mrc.ac.uk

Niacin rich diets for Pink flies

pink_fly-1410843

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.


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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)

Stats

Source: ParkinsonsUK

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

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:

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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.

601587-fig-003

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:

pink

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.
PMID: 15087508

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:

dec-2004

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.
PMID: 15596610

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.

f4-large

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.

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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:

pink1-et

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

Blood test for Parkinson’s disease?

 

blood-cells

Last week there was a press release from La Trobe University in Melbourne, Australia regarding the development of a new blood test for Parkinson’s disease. The announcement is a little bit odd as the results of the study are still being peer-reviewed (press announcements usually come after the publication of results). But the Parkinson’s community is excited by the idea of new diagnostic aids, especially those that can maybe tell us something new about the disease.

In this post, we will review what we know at present, and we will follow up this post once the results are eventually published.


As we have previously written, the diagnosis of Parkinson’s is rather difficult, with a 10-15% error rate becoming apparent when brains are analysed at the postmortem stage. Thus any new diagnostic tools/tests that can aid in this effort would be greatly appreciated.

La_Trobe_University_logo.svg

A group at La Trobe University in Melbourne have been studying the blood of people with neurodegenerative conditions, and have now announced that they may have a blood test for Parkinson’s disease.

preview

The La Trobe University team: (left to right) Professor Paul Fisher, Dr Sarah Annesley and Dr Danuta Loesch-Mdzewska. Source: La trobe

So what do we know thus far?

The test has been conducted on blood taken from a total of 38 people (29 people with Parkinson’s disease and 9 in a control group). Professor Paul Fisher – one of the lead scientists in the study – has reported that the tests have proven ‘very reliable’.

What does the test measure?

The test is apparently looking at the mitochondria in the blood cells.

And what are mitochondria?

A mitochondrion (singular) is a small structure inside a cell that is responsible for respiration and energy production. It is one of the powerhouses of the cell. Cells have lots of mitochondria (plural) because cells need lots of energy. But when the mitochondria start failing, the cell dies. As the mitochondria fails, they send out toxic chemical signals that tell the cell to begin shutting down.

biobook_cells_4

A schematic of a mitochondria, and where they are inside a cell. Source: Shmoop

The researchers at La Trobe found in their blood tests that there was no damage to the mitochondria of patients with Parkinson’s disease. That in itself is an interesting observation, but what they found next has larger implications:

“Based on the current literature we were expecting reduced oxygen consumption in the mitochondria, which leads to a buildup of toxic byproducts, but what we saw was the exact opposite,” Prof Fisher was quoted as saying. “We were able to show the mitochondria were perfectly normal but were working four times as hard, which also leads to increased production of poisonous byproducts to occur.”

A test that can measure these ‘hyperactive’ mitochondria is very useful as it can both identify people with Parkinson’s disease, but it may also help us to better understand the condition. Prof Fisher and his colleagues, in addition to taking the test forward, are also trying to understand the underlying mechanisms of the ‘hyperactive mitochondria’ – what is causing them to become the way they are.

What is going to happen now?

The scientists at La Trobe would like to repeat and expand on the results (after they are published), and the Michael J Fox foundation and Shake It Up Australia have given La Trobe University more than $640,000 to further develop the research. The plan is to now test 100 subjects – 70 people with Parkinson’s disease and a control group of 30. Prof Fisher is hoping that a test may be available for the clinic in five years time.

What about other neurodegenerative conditions?

So here’s the catch with the information provided thus far – the researchers have not had the funding to test whether this hyperactivity in the mitochondria is occurring exclusively in people with Parkinson’s. That is to say, they haven’t tested whether the effect is also present in people with other neurodegenerative diseases, such as Alzheimer’s, Huntington’s, or ALS. And this is where a little bit of the excitement comes out of the announcement.

But even if the hyperactivity in the mitochondria is shared between certain neurodegenerative diseases, a test highlighting the effect would still be very useful, especially if it can aid us in early detection of these conditions.

As we said above, we will be following this story closely and will report back here as and when information becomes available.

Stay tuned.