Tagged: PARK2

Nilotinib: the other phase II trial

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In October 2015, researchers from Georgetown University announced the results of a small clinical trial that got the Parkinson’s community very excited. The study involved a cancer drug called Nilotinib, and the results were rather spectacular.

What happened next, however, was a bizarre sequence of disagreements over exactly what should happen next and who should be taking the drug forward. This caused delays to subsequent clinical trials and confusion for the entire Parkinson’s community who were so keenly awaiting fresh news about the drug.

Earlier this year, Georgetown University announced their own follow up phase II clinical trial and this week a second phase II clinical trial funded by a group led by the Michael J Fox foundation was initiated.

In todays post we will look at what Nilotinib is, how it apparently works for Parkinson’s disease, what is planned with the new trial, and how it differs from the  ongoing Georgetown Phase II trial.


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The FDA. Source: Vaporb2b

This week the U.S. Food and Drug Administration (FDA) has given approval for a multi-centre, double-blind, randomised, placebo-controlled Phase IIa clinical trial to be conducted, testing the safety and tolerability of Nilotinib (Tasigna) in Parkinson’s disease.

This is exciting and welcomed news.

What is Nilotinib?

Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML).

What does any that mean?

Basically, it is the drug that is used to treat a type of blood cancer (leukemia) when the other drugs have failed. It was approved for treating this cancer by the FDA in 2007.

Continue reading

PARK2 and the big C

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Recently it has been announced that the Parkinson’s disease-associated gene PARK2 was found to be mutated in 1/3 of all types of tumours analysed in a particular study.

For people with PARK2 associated Parkinson’s disease this news has come as a disturbing shock and we have been contacted by several frightened readers asking for clarification.

In today’s post, we put the new research finding into context and discuss what it means for the people with PARK2-associated Parkinson’s disease.


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The As, the Gs, the Ts, and the Cs. Source: Cavitt

 

The DNA in almost every cell of your body provides the template for making a human being.

All the necessary information is encoded in that amazing molecule. The basic foundations of that blueprint are the ‘nucleotides’ – which include the familiar A, C, T & Gs – that form pairs (called ‘base pairs’) and which then join together in long strings of DNA that we call ‘chromosomes’.

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The basics of genetics. Source: CompoundChem

If DNA provides the template for making a human being, however, it is the small variations (or ‘mutations’) in our individual DNA that ultimately makes each of us unique. And these variations come in different flavours: some can simply be a single mismatched base pair (also called a point-mutation or single nucleotide variant), while others are more complicated such as repeating copies of multiple base pairs.

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Lots of different types of genetic variations. Source: Nature

Most of the genetic variants that define who we are, we have had since conception, passed down to us from our parents. These are called ‘germ line’ mutations. Other mutations, which we pick up during life and are usually specific to a particular tissue or organ in the body (such as the liver or blood), are called ‘somatic’ mutations.

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Somatic vs germ line mutations. Source: AutismScienceFoundation

In the case of germ line mutations, there are several sorts. A variant that has to be provided by both the parents for a condition to develop, is called an ‘autosomal recessive‘ variant; while in other cases only one copy of the variant – provided by just one of the parents – is needed for a condition to appear. This is called an ‘autosomal dominant’ condition.

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Autosomal dominant vs recessive. Source: Wikipedia

Many of these tiny genetic changes infer benefits, while other variants can result in changes that are of a more serious nature.

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

Approximately 15% of people with Parkinson disease have a family history of the condition – a grandfather, an aunt or cousin. For a long time researchers have noted this familial trend and suspected that genetics may play a role in the condition.

About 10-20% of Parkinson’s disease cases can be accounted for by genetic variations that infer a higher risk of developing the condition. In people with ‘juvenile-onset’ (diagnosed under the age 20) or ‘early-onset’ Parkinson’s disease (diagnosed under the age 40), genetic variations can account for the majority of cases, while in later onset cases (>40 years of age) the frequency of genetic variations is more variable.

For a very good review of the genetics of Parkinson’s disease – click here.

There are definitely regions of DNA in which genetic variations can increase one’s risk of developing Parkinson’s disease. These regions are referred to as ‘PARK genes’.

What are PARK genes?

We currently know of 23 regions of DNA that contain mutations associated with increased risk of developing Parkinson’s disease. As a result, these areas of the DNA have been given the name of ‘PARK genes’.

The region does not always refer to a particular gene, for example in the case of our old friend alpha synuclein, there are two PARK gene regions within the stretch of DNA that encodes alpha synuclein – that is to say, two PARK genes within the alpha synuclein gene. So please don’t think of each PARK genes as one particular gene.

There can also be multiple genetic variations within a PARK gene that can increase the risk of developing Parkinson’s disease. The increased risk is not always the result of one particular mutation within a PARK gene region (Note: this is important to remember when considering the research report we will review below).

In addition, some of the mutations within a PARK gene can be associated with increased risk of other conditions in addition to Parkinson’s disease.

And this brings us to the research report that today’s post is focused on.

One of the PARK genes (PARK2) has recently been in the news because it was reported that mutations within PARK2 were found in 2/3 of the cancer tumours analysed in the study.

Here is the research report:

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Title: PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation
Authors: Gupta A, Anjomani-Virmouni S, Koundouros N, Dimitriadi M, Choo-Wing R, Valle A, Zheng Y, Chiu YH, Agnihotri S, Zadeh G, Asara JM, Anastasiou D, Arends MJ, Cantley LC, Poulogiannis G
Journal: Molecular Cell, (2017) 65, 6, 999–1013
PMID: 28306514               (This article is OPEN ACCESS if you would like to read it)

The investigators who conducted this study had previously found that mutations in the PARK2 gene could cause cancer in mice (Click here to read that report). To follow up this research, they decided to screen the DNA from a large number of tumours (more than 20,000 individual samples from at least 28 different types of tumours) for mutations within the PARK2 region.

Remarkably, they found that approximately 30% of the samples had PARK2 mutations!

In the case of lung adenocarcinomas, melanomas, bladder, ovarian, and pancreatic, more than 40% of the samples exhibited genetic variations related to PARK2. And other tumour samples had significantly reduced levels of PARK2 RNA. For example, two-thirds of glioma tumours had significantly reduced levels of PARK2 RNA.

Hang on a second, what is PARK2?

PARK2 is a region of DNA that has been associated with Parkinson’s disease. It lies on chromosome 6. You may recall from high school science class that a chromosomes is a section of our DNA, tightly wound up to make storage in cells a lot easier. Humans have 23 pairs of chromosomes.

Several genes fall within the PARK2 region, but most of them are none-protein-coding genes (meaning that they do not give rise to proteins). The PARK2 region does produce a protein, which is called Parkin.

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The location of PARK2. Source: Atlasgeneticsoncology

Particular genetic variants within the PARK2 regions result in an autosomal recessive early-onset form of Parkinson disease (diagnosed before 40 years of age). One recent study suggested that as many as half of the people with early-onset Parkinson’s disease have a PARK2 variation.

Click here for a good review of PARK2-related Parkinson’s disease.

Ok, so if PARK2 was about Parkinson’s disease, what is it doing in cancer?

In Parkinson’s disease, Parkin – the protein of PARK2 – is involved with the removal/recycling of rubbish from the cell. But Parkin has also been found to have other functions. Of particular interest is the ability of Parkin to encourage dividing cells to…well, stop dividing. We do not see this function in neurons, because neurons do not divide. In rapidly dividing cells, however, Parkin can apparently stop the cells from dividing:

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Title: Parkin induces G2/M cell cycle arrest in TNF-α-treated HeLa cells
Authors: Lee MH, Cho Y, Jung BC, Kim SH, Kang YW, Pan CH, Rhee KJ, Kim YS.
Journal: Biochem Biophys Res Commun. 2015 Aug 14;464(1):63-9.
PMID: 26036576

This discovery made researchers re-designate PARK2 as a ‘tumour suppressor‘ – a gene that encodes a protein which can block the development of tumours. Now, if there is a genetic variant within a tumour suppressor – such as PARK2 – that blocks it from stopping dividing cells, there is the possibility of the cells continuing to divide and developing into a tumour.

Without a properly functioning Parkin protein, rapidly dividing cells may just keep on dividing, encouraging the growth of a tumour.

Interestingly, the reintroduction of Parkin into cancer cells results in the death of those cells – click here to read more on this.

Oh no, I have a PARK2 mutation! Does this mean I am going to get cancer?

No.

Let us be very clear: It does not mean you are ‘going to get cancer’.

And there are two good reasons why not:

Firstly, location, location, location – everything depends on where in the Parkin gene a mutation actually lies. There are 10 common mutations in the Parkin gene that can give rise to early-onset Parkinson’s disease, but only two of these are associated with an increased risk of cancer (they are R24P and R275W – red+black arrow heads in the image below – click here to read more about this).

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Comparing PARK2 Cancer and PD associated mutations. Source: Nature

Parkin (PARK2) is one of the largest genes in humans (of the 24,000 protein encoding genes we have, only 18 are larger than Parkin). And while size does not really matter with regards to genetic mutations and cancer (the actual associated functions of a gene are more critical), given the size of Parkin it isn’t really surprising that it has a high number of trouble making mutations. But only two of the 13 cancer causing mutations are related to Parkinson’s.

Thus it is important to beware of exactly where your mutation is on the gene.

Second, in general, people with Parkinson’s disease actually have a 20-30% decreased risk of cancer (after you exclude melanoma, for which there is an significant increased risk and everyone in the community should be on the lookout for). There are approximately 140 genes that can promote or ‘drive’ tumour formation. But a typical tumour requires mutations in two to more of these “driver gene” for a tumour to actually develop. Thus a Parkin cancer-related mutation alone is very unlikely to cause cancer by itself.

So please relax.

The new research published this week is interesting, but it does not automatically mean people with a PARK2 mutation will get cancer.

What does it all mean?

So, summing up: Small variations in our DNA can play an important role in our risk of developing Parkinson’s disease. Some of those Parkinson’s associated variations can also infer risk of developing other diseases, such as cancer.

Recently new research suggested that genetic variations in a Parkinson’s associated genetic region called PARK2 (or Parkin) are found in many forms of cancer. While the results of this research are very interesting, in isolation this information is not useful except in frightening people with PARK2 associated Parkinson’s disease. Cancers are very complex. The location of a mutation within a gene is important and generally more than cancer-related gene needs to be mutated before a tumour will develop.

The media needs to be more careful with how they disseminate this information from new research reports. People who are aware that they have a particular genetic variation will be sensitive to any new information related to that genetic region. They will only naturally take the news badly if it is not put into proper context.

So to the frightened PARK2 readers who contacted us requesting clarification, firstly: keep calm and carry on. Second, ask your physician about where exactly your PARK2 variation is exactly within the gene. If you require more information from that point on, we’ll be happy to help.


The banner for today’s post was sourced from Ilovegrowingmarijuana

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).

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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.

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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?

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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:

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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:

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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:

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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:

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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

Juvenile-onset Parkinson’s disease

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A community in New Brunswick (Canada) was recently shocked to discover that a 2 year old boy in their midst had been diagnosed with Parkinson’s disease (Click here to read more).

Yes, you read that correctly, it’s not a typo: a 2 year old boy.

Juvenile-onset Parkinson’s disease is an extremely rare version of the condition we discuss here at the Science of Parkinson’s. It is loosely defined as being ‘diagnosed with Parkinson’s disease under the age of 20’. The prevalence is unknown, but there is a strong genetic component to form of the condition. In today’s post we will review what is known about Juvenile-onset and look at new research about a gene that has recently been discovered to cause a type of Juvenile-onset Parkinson’s disease.


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Dr Henri Huchard. Source: Wikipedia

In 1875, Dr Henri Huchard (1844-1910; a French neurologist and cardiologist) described the first case of a child who, at just 3 years of age, presented all the clinical features of Parkinson’s disease. Since that report, there have been many studies detailing the condition that has become known as ‘juvenile-onset Parkinson’s disease’.

What is juvenile-onset Parkinson’s disease?

Basically, it is a form of Parkinson’s disease that affects children and young people under the age of 20. The defining feature is the age of onset. The average age of onset is approximately 12 years of age (with the majority of cases falling between 7 and 16 years) and males are affected by this condition more than females (at a rate of approximately 5:1).

The actual frequency of juvenile-onset parkinson’s is unknown given how rare it is. When researcher look at people with early onset Parkinson’s disease (that is diagnosis before the age of 40; approximately 5% of the Parkinson’s community), they have found that between 0.5 – 5% of that group of people were diagnosed before 20 years of age. This suggests that within just the Parkinson’s community, the frequency of juvenile-onset parkinson’s is at the most 0.25% (or 2.5 people per 1000 people with Parkinson’s). Thus it is obviously a very rare condition.

It is interesting to note that Lewy bodies (the clusters of aggregated protein that classically characterise the brains of people with Parkinson’s disease) are very rare in cases of juvenile-onset parkinson’s disease. To our knowledge there has been only one case of Lewy bodies in juvenile-onset parkinson’s disease (Click here to read more on this). This suggests that the juvenile-onset form of Parkinson’s disease may differ from other forms of the condition in its underlying biology.

Do we know what causes juvenile-onset parkinson’s disease?

There is a very strong genetic component to juvenile-onset parkinson’s disease. In fact, the incidence of Parkinsonism in relatives of people with juvenile-onset parkinson’s disease is higher than in the general public AND in the relatives of people with other forms of Parkinson’s disease.

Genetic mutations in three genes are recognised as causing juvenile-onset Parkinson’s disease. The three genes are known to the Parkinson’s world as they are all PARK genes (genetic variations that are associated with Parkinson’s). Those three genes are:

  • Parkin (PARK2)
  • PTEN-induced putative kinase 1 (PINK1 or PARK6)
  • DJ1 (PARK7)

In juvenile-onset Parkinson’s disease, all of these mutations are associated with autosomal recessive – meaning that two copies of the genetic variation must be present in order for the disease to develop.

Parkin mutations account for the majority of juvenile-onset Parkinson’s disease cases. Affected individuals have a slowly progressing condition that is L-dopa responsive. Dystonia (abnormal muscle tone resulting in muscular spasm and abnormal posture) is very common at the onset of the condition, particularly in the lower limbs.

Can the condition be treated with L-dopa?

The answer is: ‘Yes, but…’

L-dopa (or dopamine replacement) treatment is the standard therapy for alleviating the motor features of Parkinson’s disease.

The majority of people with juvenile-onset parkinson’s respond well to L-dopa, but in the Parkin mutation version individuals will typically begin to experience L-dopa-induced motor fluctuations (dyskinesias) early in that treatment regime.

What research is currently being done on this condition?

Given that cases are so very rare and so few, it is difficult to conduct research on this population of individuals. Most of the research that is being conducted is focused on the genetics underlying the condition.

And recent that research lead to the discovery of a new genetic variation that causes juvenile-onset Parkinson’s disease:

Juvenile

Title: Discovery of a frameshift mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion molecule, as causal for autosomal-recessive juvenile Parkinsonism.
Authors: Sudhaman S, Prasad K, Behari M, Muthane UB, Juyal RC, Thelma BK.
Journal: Journal Med Genet. 2016 Jul;53(7):450-6.
PMID: 26864383           (This article is OPEN ACCESS if you would like to read it)

The researchers who wrote this article were presented with a 10 member Indian family from Aligarh, Uttar Pradesh. Of the 8 children in the  family, 3 were affected by Parkinsonian features (tremor, slowness, rigidity and gait problems) that began between 13 and 17 years of age. The researchers conducted DNA sequencing and found that none of the three affected siblings had any of the known Juvenile-onset Parkinson’s disease genetic mutations (specifically, mutations in the genes PARK2, PINK1and DJ1).

They then compared the DNA from the three siblings with the rest of the family and found a genetic variant in a gene called podocalyxin-like (or PODXL). It must be noted that PODXL is a completely novel gene in the world of Parkinson’s disease research, which makes it very interesting. PODXL has never previously been associated with any kind of Parkinson’s disease, though it has been connected with two types of cancer (embryonal carcinoma and periampullary adenocarcinoma).

The researchers then turned to their genetic database of 280 people with Parkinson’s disease have had their genomes sequenced. The researchers wanted to determine if any genetic variants in the PODXL gene were present in other suffers of Parkinson’s disease, but had not been picked up as a major contributing factor. They found three unrelated people with PODXL mutations. All three had classical Parkinson’s features, and were negative for mutations in the Parkin, PINK1 and DJ1 genes.

The researchers concluded that the PODXL gene may be considered as a fourth causal gene for Juvenile-onset Parkinson’s disease, but they indicated that further investigations in other ethnic groups are required.

 


The banner for today’s post was sourced from ClipArtBest

The Autistic spectrum and Parkinson’s disease

The word Autism on a cork notice board

In August of 2015, groups of scientists from North Carolina and Perth (Australia) published a report together in which they noted the high occurrence of Parkinson’s-like features in aging people with Autism.

In this post we will have a look at what links (if any) there may be between Autism and Parkinson’s disease.


Recent estimates suggest that the prevalence of Autistic Spectrum Disorders in US children is approximately 1.5 %. Autism is generally associated with children, and in this way it is almost a mirror opposite of Parkinson’s disease (which is usually associated with the elderly). A fair number of people who were diagnosed with Autism early in their lives are now reaching the age of retirement, but we know very little about what happens in this condition in the aged.

What is Autism?

This is one of those questions that gets people into trouble. There is a great deal of debate over how this condition should be defined/described. We here at SoPD will chose to play it safe and provide the UK National Health System (NHS)‘s description:

Autism spectrum disorder (ASD) is a condition that affects social interaction, communication, interests and behaviour. In children with ASD, the symptoms are present before three years of age, although a diagnosis can sometimes be made after the age of three. It’s estimated that about 1 in every 100 people in the UK has ASD. More boys are diagnosed with the condition than girls.

Wikipedia also has a very thorough page Autism

So what was reported in the study finding a connection between Autism and Parkinson’s disease?

Last year two groups of researchers (from North Carolina, USA and Perth, Australia) noticed an interesting trend in some of the aging Autistic subjects they were observing.

They published their findings in the Journal of Neurodevelopmental disorders:

Autism-title1

Title: High rates of parkinsonism in adults with autism.
Authors: Starkstein S, Gellar S, Parlier M, Payne L, Piven J.
Journal: Journal of Neurodev Disord. 2015;7(1):29.
PMID: 26322138         (This report is OPEN ACCESS if you would like to read it)

The article reports the findings of two studies:

Study I (North Carolina) included 19 men with Autism (with an average age of 57 years). When the researchers investigated the cardinal features of Parkinson’s disease, they found that 22 % (N = 4) of the subjects exhibited bradykinesia (or slowness of movement), 16 % (N = 3) had a resting tremor, 32 % (N = 6) displayed rigidity, and 15 % (N = 2) had postural instability issues.

In fact, three of the 19 subjects (16 %) actually met the criteria for a full diagnosis of Parkinson’s disease (one of who was already responding well to L-dopa treatment).

Study II (Perth) was a larger study, involving 32 men and 5 women (with an average age of 51 years). 46 % (N = 17) of the subjects in this study exhibited bradykinesia, 19 % (N = 7) had a resting tremor, 19 % (N = 7) displayed rigidity, and 19 % (N = 7) had postural instability problems. In study II, 12 of the 37 subjects (32 %) met the full diagnostic criteria for Parkinson’s disease.

Given this collective result, the researchers concluded that there may well be an increased frequency of Parkinsonism in the aged people with Autism. They emphasize, however, the need to replicate the study before definitive conclusions can be made.

So how could this be happening?

The short answer is: we don’t have a clue.

The results of this study need to be replicated a few times before we can conclusively say that there is a connection. There are, however, some interesting similarities between Autism and Parkinson’s disease, for example (as the NHS mentioned above) males are more affected than females in both conditions.

There are genetic variations that both Parkinson’s and Autism share. Approximately 10-20% of people with Parkinson’s disease have a genetic variation in one of the PARK genes (we have discussed these before – click here to read that post). The genetics of Autism are less well understood. If you have one child with Autism, the risk for the next child also having the condition is only 2-6% (genetically speaking, it should be a 25-50% level of risk).

There are, however, some genes associated with Autism and one of those genes is the Parkinson’s associated gene, PARK2. it has previously been reported that variants in the PARK2 gene (Parkin) in children with Autism (click here for more on this).

It would be interesting to have a look at the brains of aged people with Autism. This could be done with brain scans (DAT-SCAN), but also at the postmortem stage to see if their brains have alpha synuclein clusters and Lewy bodies – the pathological characteristics of Parkinson’s disease. These studies may well be underway – we’ll keep an eye out for any reports.

Alternative explanations?

There are alternative explanations for the connection between Autism and Parkinson’s disease suggested by this study. For example, 36 of the 56 subjects involved in the two studies were on medication for their Autism (the medication is called neuroleptics). Those medications did not appear to explain the rates of parkinsonism in either study (after excluding subjects currently on neuroleptic medications, the frequency of parkinsonism was still 20 %). Most of the subjects in both studies have been prescribed neuroleptics at some point in their lives. Thus it is possible that long-term use of neuroleptics may have had the effect of increasing the risk for parkinsonism later in life. This is pure speculation, however, and yet to be tested. Any future studies would need to investigate this as a possibility.


EDITOR’S NOTE: If you have a child or loved one on the Autism spectrum, it is important to understand that the study summarised here are novel results that are yet to be replicated. And if it turns out that adults with Autism do have a higher risk of developing Parkinson’s disease it does not necessarily mean that they will – simply that they are at greater risk than normal. It is best to consult a medical practitioner if you have further concerns.


The banner at the  today’s post was sourced from Sailing Autistic Seas.