There is a protein in most of the cells in your body called “PTEN-induced putative kinase 1″ (or simply PINK1). It plays an important role in keeping your cells healthy.
Genetic variations in the PINK1 gene have been shown to increase ones risk of developing Parkinson’s.
This week researchers have identified a method by which the function of the PINK1 protein can be inhibited and this results in increased vulnerability to Parkinson’s. In this post, we will look at what PINK1 does, how it is inhibited, and what this could mean for the Parkinson’s community.
Mitochondria (green) in health cells (left) and in unhealthy cells (right).
The nucleus of the cell is in blue. Source: Salk Institute
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 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 which is the waste disposal system of each cell).
What does this have to do with Parkinson’s disease?
The title of this post probably reads like the mad, drug-fuelled scream of a drunk Saturday night party animal, but the elements of it may be VERY important for a particular kind of Parkinson’s disease.
Mutations in a gene called DJ-1 can cause an early onset form of Parkinson’s disease. The protein of DJ-1 plays an important role in how cells handle oxidative stress – or the increase in damaging free radicals (explained below).
This week researchers announced that they have found an interesting new therapeutic target for people with DJ-1 associated Parkinson’s disease: A chemical called Isocitrate.
In this post, we will discuss what DJ-1 is involved with Parkinson’s disease, how isocitrate helps the situation, and what the results of new research mean for future therapeutic strategies.
In 2017, we are not only observing the 200 year anniversary of the first description of Parkinson’s disease (by one Mr James Parkinson), but also the 20th anniversary of the discovery of the first genetic variation associated with the condition (Click here to read more about that). Our understanding of the genetics of Parkinson’s disease since 1997, has revolutionised the way we look at Parkinson’s disease and opened new doors that have aided us in our understanding.
During the last 20 years, we have identified numerous sections of DNA (these regions are called genes) where small errors in the genetic coding (mutations or variants) can result in an increased risk of developing Parkinson’s disease. As the graph below indicates, mutations in some of these genes are very rare, but infer a very high risk, while others are quite common but have a low risk of Parkinson’s disease.
The genetics of PD. Source: Journal of Parkinson’s disease
Some of the genetic mutation need to be provided by both the parents for Parkinson’s to develop (an ‘autosomal recessive‘ mutation – the yellow circles in the graph above); while in other cases the genetic variant needs only to be provided by one of the parents (an ‘autosomal dominant’ mutation – the blue circles). Many of the genetic mutations are very common and simply considered a region of increased risk (green circles).
Importantly, all of these genes provide the instructions for making a protein – which are the functional parts in a cell. And each of these proteins have specific roles in biological processes. These functions tell us a little bit about how Parkinson’s disease may be working. Each of them is a piece of the jigsaw puzzle that we are trying to finish. As you can see in the image below, many of the genes mentioned in the graph above give rise to proteins that are involved in different parts of the process of autophagy – or the waste disposal system of the cell. You may notice that some proteins, like SCNA (otherwise known as alpha synuclein), are involved in multiple steps in this process.
The process of autophagy. Source: Nature
In today’s post we are going to look at new research regarding just one of these genes/proteins. It is called DJ-1, also known as Parkinson disease protein 7 (or PARK7).
What is DJ-1?
In this post I review recently published research describing interesting new gene therapy tools.
“Gene therapy” involved using genetics, rather than medication to treat conditions like Parkinson’s disease. By replacing faulty sections of DNA (or genes) or providing supportive genes, doctors hope to better treat certain diseases.
While we have ample knowledge regarding how to correct or insert genes effectively, the problem has always been delivery: getting the new DNA into the right types of cells while avoiding all of the other cells.
Now, researchers at the California Institute of Technology may be on the verge of solving this issue with specially engineered viruses.
Gene therapy. Source: yourgenome
When you get sick, the usual solution is to visit your doctor. They will prescribe a medication for you to take, and then all things going well (fingers crossed/knock on wood) you will start to feel better. It is a rather simple and straight forward process, and it has largely worked well for most of us for quite some time.
As the overall population has started to live longer, however, we have become more and more exposed to chronic conditions which require long-term treatment regimes. The “long-term” aspect of this means that some people are regularly taking medication as part of their daily lives. In many cases, these medications are taken multiple times per day.
An example of this is Levodopa (also known as Sinemet or Madopar) which is the most common treatment for the chronic condition of Parkinson’s disease. When you swallow your Levodopa pill, it is broken down in the gut, absorbed through the wall of the intestines, transported to the brain via our blood system, where it is converted into the chemical dopamine – the chemical that is lost in Parkinson’s disease. This conversion of Levodopa increases the levels of dopamine in your brain, which helps to alleviate the motor issues associated with Parkinson’s disease.
Levodopa. Source: Drugs
This pill form of treating a disease is only a temporary solution though. People with Parkinson’s disease – like other chronic conditions – need to take multiple tablets of Levodopa every day to keep their motor features under control. And long term this approach can result in other complications, such as Levodopa-induced dyskinesias in the case of Parkinson’s.
Yeah, but is there a better approach?
Some researchers believe there is. But we are not quite there yet with the application of that approach. Let me explain:
Two months ago a research report was published in the scientific journal ‘Nature’ and it caused a bit of a fuss in the embryonic stem cell world.
Embryonic stem (ES) cells are currently being pushed towards the clinic as a possible source of cells for regenerative medicine. But this new report suggested that quite a few of the embryonic stem cells being tested may be carrying genetic variations that could be bad. Bad as in cancer bad.
In this post, I will review the study and discuss what it means for cell transplantation therapy for Parkinson’s disease.
For folks in the stem cell field, the absolute go-to source for all things stem cell related is Prof Paul Knoepfler‘s blog “The Niche“. From the latest scientific research to exciting new stem cell biotech ventures (and even all of the regulatory changes being proposed in congress), Paul’s blog is a daily must read for anyone serious about stem cell research. He has his finger on the pulse and takes the whole field very, very seriously.
For a long time now, Paul has been on a personal crusade. Like many others in the field (including yours truly), he has been expressing concern about the unsavoury practices of the growing direct-to-consumer, stem cell clinic industry. You may have seen him mentioned in the media regarding this topic (such as this article).
The real concern is that while much of the field is still experimental, many stem cell clinics are making grossly unsubstantiated claims to draw in customers. From exaggerated levels of successful outcomes (100% satisfaction rate?) all the way through to talking about clinical trials that simply do not exist. The industry is badly (read: barely) regulated which is ultimately putting patients at risk (one example: three patients were left blind after undergoing an unproven stem cell treatment – click here to read more on this).
While the stem cell research field fully understands and appreciates the desperate desire of the communities affected by various degenerative conditions, there has to be regulations and strict control standards that all practitioners must abide by. And first amongst any proposed standards should be that the therapy has been proven to be effective for a particular condition in independently audited double blind, placebo controlled trials. Until such proof is provided, the sellers of such products are simply preying on the desperation of the people seeking these types of procedures.
One of the most common observations that people make when they attend a Parkinson’s disease support group meeting is the huge variety of symptoms between sufferers.
Some people affected by this condition are more tremor dominant, while others have more pronounced gait (or walking) issues. In addition, some people have an early onset version, while others has a very later onset. What could explain this wide range of features?
A group of Stanford researchers have recently proposed an interesting new idea regarding our understanding of genetics that could partly explain some of this variability. In todays post I speculate on whether their idea could be applied to Parkinson’s disease.
Earlier this year an interesting study was published in the prestigious journal Nature on the topic of the genetics of height (yes height. Trust me, I’m going somewhere with this):
Title: Rare and low-frequency coding variants alter human adult height
Authors: Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR, Fine RS, Lu Y, Schurmann C,………at least 200 additional authors have been deleted here in order to save some space…….EPIC-InterAct Consortium; CHD Exome+ Consortium; ExomeBP Consortium; T2D-Genes Consortium; GoT2D Genes Consortium; Global Lipids Genetics Consortium; ReproGen Consortium; MAGIC Investigators, Rotter JI, Boehnke M, Kathiresan S, McCarthy MI, Willer CJ, Stefansson K, Borecki IB, Liu DJ, North KE, Heard-Costa NL, Pers TH, Lindgren CM, Oxvig C, Kutalik Z, Rivadeneira F, Loos RJ, Frayling TM, Hirschhorn JN, Deloukas P, Lettre G.
Journal: Nature. 2017 Feb 9;542(7640):186-190.
In this study, the researchers – who are part of the GIANT consortium – were analysing DNA collected from over 700,000 people and trying to determine what genetic differences could influence height.
Height is not important for music. Source: Imgur
Why study height?
Good question. There are several reasons:
Firstly, it is easy to accurately measure. Second, the researchers believed that if we can master the complex genetics of something simple like height maybe what we learn will give us a blueprint for how we should study more complex medical disorders that have thus far eluded our complete understanding.
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.
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:
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.
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.
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.
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.
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’.
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.
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.
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.
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:
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.
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:
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.
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?
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).
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
Interesting new data published today regarding the curious connection between Parkinson’s disease and melanoma.
It was interesting because the data suggests that there is no genetic connection. No obvious connection that is.
In this post we will review the study and discuss what it all means.
Melanoma. Source: Wikipedia
Question 1.: why are people with Parkinson’s disease are 2-8 times more likely to develop melanoma – the skin cancer – than people without Parkinson’s?
Question 2.: why are people with melanoma almost 3 times more likely to develop Parkinson’s disease than someone without melanoma?
This topic is an old favourite here at the SoPD, and we have discussed it several times in previous posts (Click here and here to read those posts). It is a really good mystery. A lot of people have looked at this issue and the connection between the two conditions has not been immediately forthcoming.
When the genetics mutations of both conditions were previously analysed, it was apparent that none of the known Parkinson’s mutations make someone more susceptible to melanoma, and likewise none of the melanoma-associated genetic mutations make a person vulnerable to Parkinson’s disease (Meng et al 2012;Dong et al 2014; Elincx-Benizri et al 2014).
So what was published today?
New genetic data! Rather than simplifying things, however, this new data has simply made the mystery….well, more of a mystery. The publication in question is:
Title: Rare variants analysis of cutaneous malignant melanoma genes in Parkinson’s disease.
Authors: Lubbe SJ, Escott-Price V, Brice A, Gasser T, Pittman AM, Bras J, Hardy J, Heutink P, Wood NM, Singleton AB, Grosset DG, Carroll CB, Law MH, Demenais F, Iles MM; Melanoma Meta-Analysis Consortium, Bishop DT, Newton-Bishop J, Williams NM, Morris HR; International Parkinson’s Disease Genomics Consortium.
Journal: Neurobiol Aging. 2016 Jul 28.
PMID: 27640074 (This article is OPEN ACCESS if you would like to read it)
Given that previous studies have suggested that there are no obvious genetic mutations connecting Parkinson’s disease with melanoma, the researchers in this study looked for very rare genetic variations in 29 melanoma-associated genes. They did this analysis on a very large pool of genetic data, from 6875 people with Parkinson’s disease and 6065 normal healthy control subjects.
What the researchers found was only very weak connections between two conditions, based on only a few of these genetic mutations (none of which were statistically significant, which means that they could be due to chance).
One very rare genetic mutation in a gene called TYR p.V275F is very interesting. It was found to be more common in people with Parkinson’s disease than controls in 3 independent groups of data. The gene TYR produces a protein called Tyrosinase, which an important ‘rate-limiting enzyme’ in biological production in both neuromelanin and dopamine (the chemical critically associated with Parkinson’s disease).
So what does this mean?
This data suggests that the connection between Parkinson’s disease and melanoma is not due to a known shared genetic mutation. This conclusion, however, leaves open many alternative possibilities. One such possibility involves the vast pieces of human DNA that are described as ‘non-coding‘. These are sections of DNA that will produce a piece of RNA, but that RNA will not be used to produce a protein (as is normal in biology 101). That non-coding RNA will, however, have functions in regulating the activity on sections of DNA or other RNAs (yeah, I know. It’s complicated. Even for me!). Importantly, these non-coding RNA can play a role in diseases. For example, it was discovered a few years ago that a non-coding RNA called BACE1-AS is produced in very large amounts in patients with Alzheimer’s disease (Click here for more on this). We are simply speculating here though.
The scientists who published the research today suggest that they will further investigate and better characterise the interesting link between the gene TYR and Parkinson’s disease, and they will now broaden their analysis of genetic regions that could be influencing the curious connection between Parkinson’s disease and melanoma. Rather than simply focusing on known genetic mutations (common or rare), they will start to dig deeper into our DNA to see what else may underlie the connection between these two conditions.
Watch this space.
The banner for today’s post was sourced from the Huffington Post
The genetics of any disease is very complicated. We are, however, gradually identifying the genetic mutations/variations that are associated with Parkinson’s disease and coming to understand that role of those genes in the condition. This week, researchers have identified a mutation underlying one form of Parkinson’s disease, which is associated with the name PARK16.
In this post we will review what the scientists have found and what it means.
A map of some of the genetic interactions associated with Parkinson’s disease. Source: Pubmed
As the image above demonstrates the genetic interactions underlying some forms of Parkinson’s disease are extremely complicated. And it is important to note, dear reader, that that schematic provides only a partially completed picture. It maps out only a portion of the interactions that we know of, and we can only guess at the interactions that we don’t know of. Complicated right?
Approximately 10-15% of cases of Parkinson’s disease are associated with a genetic variation in the DNA that renders an individual vulnerable to the condition.
The region of DNA in which a mutations occurs is called the ‘Locus’. There are more than 20 loci (these regions of mutations) now associated with Parkinson’s disease. The loci are referred to as ‘PARK genes’.
What are the PARK genes?
Below is a table of the first 15 PARK genes to be associated with Parkinson’s disease:
A list of the PARK genes. Source: JKMA
The PARK genes in the table are numbered 1 to 15 (16-20 are not mentioned here), and their genetic location is indicated under the label ‘Chromosome’ (this tells us which chromosome the locus is located on and where on that chromosome it is). The specific gene and protein that are affected by the mutation are also labelled (for example the gene (and protein) associated with PARK8 is Lrrk2). It is interesting to note that the gene responsible for making the protein alpha synuclein (SNCA) has two PARK gene loci within it (PARK 1 and PARK4), further emphasizing the importance of this gene in the disease.
You may also notice that there are a lot of unknowns under the labels ‘protein function’ and ‘Pathology’ (with regards to Parkinson’s disease), this is because we are still researching these genes. Furthermore, PARK3 and PARK11 both have question marks beside the genes associated with these loci, indicating that we are still not sure if these are the genes responsible for the dysfunction we observed in these forms of Parkinson’s disease.
Obviously the PARK genes list is a work in progress.
That said, this week researchers from the University of Tehran (Iran) published a report about the gene they believe is responsible for the dysfunction associated with PARK16 mutations:
Title: Mutation in ADORA1 identified as likely cause of early-onset parkinsonism and cognitive dysfunction.
Author: Jaberi E, Rohani M, Shahidi GA, Nafissi S, Arefian E, Soleimani M, Moghadam A, Arzenani MK, Keramatian F, Klotzle B, Fan JB, Turk C, Steemers F, Elahi E.
Journal: Mov Disord. 2016 May 2.
The researchers had two siblings (brothers) referred to them that had been diagnosed with early onset Parkinson’s disease (2 siblings from a family of 8 children). Both of the siblings were in their early 30s, but had exhibited Parkinson’s-like features since their early 20s. They had responded to L-dopa therapy, but involuntary movements (L-dopa-induced dyskinesias) had started to appear after just 2 years of treatment.
Naturally the researchers were keen to determine if there was a genetic reason for this situation. To this end, they conducted whole genome analysis to determine what genetic variations the two siblings shared.
They took DNA from white blood cells of the 10 family members (two parents and eight children), and sequenced the genomes for analysis. What they found was two regions of DNA that were the same in the two affected siblings, but different in the rest of the family. In one of these regions was in the gene ADORA1, which encodes a receptor for a particular protein that can influence dopamine release. Importantly, the ADORA1 gene is located within the domain of the PARK16 locus.
When the researcher checked the sibling’s genetic variation inside the ADORA1 gene on a database of 60,000 normal individuals, they found only one other individual who was partially affected by it, suggesting that this mutation is very rare. Based on these findings, the researchers concluded that variations in ADORA1 may explain some of the cases of PARK16 -associated Parkinson’s disease.
So what does it all mean?
It means that we have another piece of the puzzle, and each week other pieces are falling into place. ADORA1 may not be the only genetic variant within the PARK16 locus, but it will explain some cases of PARK16 Parkinson’s disease. Next we need to work out what the variation does to the gene function of ADORA1.
And that will hopefully be a future blog post.
There was an interesting new study published yesterday:
Title: Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns.
Author: Sanchez-Mut JV, Heyn H, Vidal E, Moran S, Sayols S, Delgado-Morales R, Schultz MD, Ansoleaga B, Garcia-Esparcia P, Pons-Espinal M, de Lagran MM, Dopazo J, Rabano A, Avila J, Dierssen M, Lott I, Ferrer I, Ecker JR, Esteller M.
Journal: Transl Psychiatry. 2016 Jan 19;6:e718. doi: 10.1038/tp.2015.214.
PMID: 26784972 – this article is OPEN ACCESS if you would like to read it.
The researchers were curious to look for common genetic markers between the major neurodegenerative disease. It is often forgotten that the different neurodegenerative conditions, such as Alzheimer’s disease and Parkinson’s disease, share some common pathological features (the characteristic signs of the diseases in the brain).
For example, when you look at the brains of people with Alzheimer’s disease, approximately 50% of them will also have the alpha-synuclein-containing ‘Lewy bodies’ in their brains, which are more commonly associated with Parkinson’s disease. Likewise, Beta-amyloid plaques and neurotangles, which are characteristic features of Alzheimer’s disease are commonly found in Parkinson’s disease brains (click here and click here for more on this topic).
To find these shared genetic markers, the researcher extracted DNA from the prefrontal cortex (Brodmann area 9) of the brains of people with Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease and Alzheimer-like neurodegenerative profile associated with Down’s syndrome samples (more than 75 percent of people with Down Syndrome aged 65 and older develop Alzheimer’s disease – click here for more on this).
Importantly, the researchers were looking at DNA methylation, which is a commonly used tool that allows a cell to fix genes in the “off” position. That is to say, the gene can not be activated. Thus the researchers were looking for regions of DNA that have to closed down.
They found that a very defined set of genes are turned off in these neurodegenerative disorders, suggesting that these condition might have similar underlying mechanisms or processes that subsequently develop into different clinical entities. These newly identified regions of DNA methylation will be further investigated with the goal that one day they may be used as biomarkers in diagnosis and also as potential new targets for the regenerative therapies.