Tag: variant

The other anniversary: 20 years of Alpha Synuclein

~ Simon ~ 11 Comments

20_years1

On the 27th June, 1997, a research report was published in the prestigious scientific journal ‘Science’ that would change the world of Parkinson’s disease research forever.

And I am not exaggerating here.

The discovery that genetic variations in a gene called alpha synuclein could increase the risk of developing Parkinson’s disease opened up whole new areas of research and eventually led to ongoing clinical trials of potential therapeutic applications.

Todays post recounts the events surrounding the discovery, what has happened since, and we will discuss where things are heading in the future.

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Source: listchallenge

It is fair to say that 1997 was an eventful year.

In world events, President Bill Clinton was entering his second term, Madeleine Albright became the first female Secretary of State for the USA, Tony Blair became the prime minister of the UK, and Great Britain handed back Hong Kong to China.

1997_Clinton_Inauguration_-_Swearing-in_Ceremony

#42 – Bill Clinton. Source: Wikipedia

In the world of entertainment, author J. K. Rowling’s debut novel “Harry Potter and the Philosopher’s Stone” was published by Bloomsbury, and Teletubbies, South Park, Ally McBeal, and Cold Feet (it’s a British thing) all appeared on TV for the first time, amusing and entertaining the various age groups associated with them.

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South Park. Source: Hollywoodreporter

Musically, rock band Blur released their popular hit song ‘Song 2‘ (released 7th April), “Bitter Sweet Symphony” by the Verve entered the UK charts at number 2 in June, and rapper Notorious B.I.G. was killed in a drive by shooting. Oh, and let’s not forget that “Tubthumping” (also known as “I Get Knocked Down”) by Chumbawamba was driving everybody nuts for its ubiquitous presence.

And at the cinemas, no one seemed to care about anything except a silly movie called Titanic.

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Titanic. Source: Hotspot

Feeling old yet?

Continue reading “The other anniversary: 20 years of Alpha Synuclein” →

The autoimmunity of Parkinson’s disease?

~ Simon ~ 12 Comments

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.

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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 “The autoimmunity of Parkinson’s disease?” →

On the hunt: Parkure

~ Simon ~ 5 Comments

Lysimachos-zografos-naturejobs-blog

This is Lysimachos.

Pronounced: “Leasing ma horse (without the R)” – his words not mine.

He is one of the founders of an Edinburgh-based biotech company called “Parkure“.

In today’s post, we’ll have a look at what the company is doing and what it could mean for Parkinson’s disease.

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Source: Parkure

The first thing I asked Dr Lysimachos Zografos when we met was: “Are you crazy?”

Understand that I did not mean the question in a negative or offensive manner. I asked it in the same way people ask if Elon Musk is crazy for starting a company with the goal of ‘colonising Mars’.

In 2014, Lysimachos left a nice job in academic research to start a small biotech firm that would use flies to screen for drugs that could be used to treat Parkinson’s disease. An interesting idea, right? But a rather incredible undertaking when you consider the enormous resources of the competition: big pharmaceutical companies. No matter which way you look at this, it has the makings of a real David versus Goliath story.

But also understand this: when I asked him that question, there was a strong element of jealousy in my voice.

Logo_without_strapline_WP

Incorporated in October 2014, this University of Edinburgh spin-out company has already had an interesting story. Here at the SoPD, we have been following their activities with interest for some time, and decided to write this post to make readers aware of them.

Continue reading “On the hunt: Parkure” →

PARK2 and the big C

~ Simon ~ 1 Comment

cancer

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:

MolCell2

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.

PARK2Fig1

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:

divide

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

Chromosome 22 and Parkinson’s disease

~ Simon ~ 1 Comment

A wise man once told me:

“When trying to understand genetics, think of DNA as the stream of words in a book. The nucleotides (A, G, T and C) are the individual letters. These ‘letters’ collect together to make up the genes (the sentences) which give the  book meaning and convey information. And the chromosomes are the chapters in that book.

Some of these ‘books’ are short reads – the fly has only 139.5 million nucleotides (‘words’) and 15,682 genes (sentences) spread across just 4 chromosomes (‘chapters’), while others are long books – humans = 3 billion words, divided into 22,000 sentences, and 23 chapters.

They were helpful words – putting things in perspective – and I hope that they might aid you dear reader as we tackle the topic of this post – a genetic mutation in a particular location of chromosome 22 and its relationship with Parkinson’s disease.

Oh, and do not be fooled into thinking that size matters when it comes to chromosomes. The mighty hedgehog and faultless pigeon have almost twice as many chromosomes as we do (45 and 40 pairs, respectively), and yet…

 

As most of you will be aware, human beings have 23 pairs of chromosomes.

Chromosomes are a concept that many people are aware of (a pub quiz type of topic), but what are they?

What exactly is a chromosome?

In a nutshell, a chromosome is a very efficient way of packing a lot of DNA into a cell.

Within most of the cells in your body, DNA is densely coiled into discrete packages called chromosomes. Without such packaging, the stringy DNA molecules would be too long to fit inside the cell. In fact, if you uncoiled all of the DNA molecules in a single human cell and placed them end-to-end, they would stretch for at least 6 feet. And that’s just for one cell – remember that the humans have approx. 40 trillion cells in their body!

CDR761781 A schematic demonstrating the arrangement of DNA- Genes-Chromosomes. Source: cancergenome.nih.gov

When a cell is not dividing, the chromosomes usually sit in the nucleus of the cell in loose strands called chromatin. When the cell decides to divide, the chromatin condenses and wrap up very tightly, becoming chromosomes. Both loose chromatin and tightly wound chromosomes are very difficult to see, even with a microscope.

Chromosomes come in pairs – one set of 23 chromosomes from each parent, giving us a total of 46 chromosomes per cell. All of these pairs reside inside the nucleus of each cell, where their DNA is read and instructions (RNA) are sent off to be made into proteins which performs functions within the cell.

Within the DNA in the chromosomes there are sometimes mistakes (think of them as spelling mistakes in the book example we mentioned above). The mistakes are called ‘mutations’ or variants. They can involve sections of DNA being absent or sections of DNA being replicated multiple times.

This week new research was published dealing with Parkinson’s disease and a mutation in chromosome 22.

What do we know about Chromosome 22?

Chromosome 22 is the second smallest human chromosome, being only slightly larger than chromosome 21. Chromosome 22 spans approximately 50 million DNA base pairs and represents 1.5-2% of the total DNA in each cell.

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The 23 chromosomes of humans (this set is from a male). Chromosome 22 is highlighted. Source: Wikipedia

There are approx. 1000 genes on chromosome 22. The functions of many of these genes (what they tell the cell/body to do) is still being determined. Mutations in some of those genes, however, are associated with certain diseases. One particular disease associated with Chromosome 22 is called chromosome 22q11.2 deletion syndrome.

What is 22q11.2 deletion syndrome?
Chromosome 22q11.2 deletion syndrome (also known as DiGeorge syndrome) is a condition that arises from a section of chromosome 22 being absent. The ’22q11.2′ code part of the name relates to the specific location on chromosome 22 where the missing sections become apparent. About 87% of deletions occur within a 3 million base pair (nucleotides) region in the middle of one copy of chromosome 22 in each cell (remember that chromosomes come in pairs). The region contains at least 52 known genes.

Given the number of possible gene affected, there are numerous clinical features associated with 22q11.2 deletion syndrome, including heart defects, an opening in the roof of the mouth (a cleft palate), subtle facial features, learning issues, and low calcium levels.

Small ‘micro deletions’ within chromosome 22 are some of the most frequent known deletions found in human beings, occurring in about 25 in 100 000 people. These micro deletions are inherited from an affected parent in 5–10% of cases, while the rest occur spontaneously.

 

So what does Chromosome 22 have to do with Parkinson’s disease?

In 2009, this research report was published:

Zaleski-title

Title: The co-occurrence of early onset Parkinson disease and 22q11.2 deletion syndrome.
Authors: Zaleski C, Bassett AS, Tam K, Shugar AL, Chow EW, McPherson E.
Journal: Am J Med Genet A. 2009 Mar;149A(3):525-8.
PMID: 19208384

In this report the researchers described two patients, both with chromosome 22q11.2 deletion syndrome and early onset Parkinson’s disease (diagnosed before 45 years of age). The researchers suggested that this co-occurrence of chromosome 22q11.2 deletion syndrome and Parkinson’s disease in two unrelated patients was unlikely to be coincidence (given the low frequency of the conditions).

That first study was followed up by a second study:

Butcher-title

Title: Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications.
Authors: Butcher NJ, Kiehl TR, Hazrati LN, Chow EW, Rogaeva E, Lang AE, Bassett AS.
Journal: JAMA Neurol. 2013 Nov;70(11):1359-66.
PMID: 24018986

In this report, the scientists conducted an observational study of the occurrence of Parkinson’s disease in the world’s largest cohort of well-characterized adults with a chromosome 22q11.2 deletion syndrome (n = 159; age range = 18.1-68.6 years). They found that people with chromosome 22q11.2 deletion syndrome had a significantly elevated occurrence of Parkinson’s disease compared with standard population estimates.

Curiously, they suggested that the common use of antipsychotics in patients with chromosome 22q11.2 deletion syndrome (to manage associated psychiatric symptoms) delayed diagnosis of Parkinson’s disease by up to 10 years. And in postmortem analysis of the brains of people with both conditions, they found the loss of dopamine neurons and the occurrence of Lewy bodies – characteristic features of Parkinson’s disease.

This was proof that people with chromosome 22q11.2 deletion syndrome were more vulnerable to developing Parkinson’s disease. But what about people with Parkinson’s disease? Do they have deletions with chromosome 22q11.2?

This week we got the answer to that question:

Mok-title

Title: Deletions at 22q11.2 in idiopathic Parkinson’s disease: a combined analysis of genome-wide association data.
Authors: Mok KY, Sheerin U, Simón-Sánchez J, Salaka A, Chester L, Escott-Price V, Mantripragada K, Doherty KM, Noyce AJ, Mencacci NE, Lubbe SJ; International Parkinson’s Disease Genomics Consortium (IPDGC), Williams-Gray CH, Barker RA, van Dijk KD, Berendse HW, Heutink P, Corvol JC, Cormier F, Lesage S, Brice A, Brockmann K, Schulte C, Gasser T, Foltynie T, Limousin P, Morrison KE, Clarke CE, Sawcer S, Warner TT, Lees AJ, Morris HR, Nalls MA, Singleton AB, Hardy J, Abramov AY, Plagnol V, Williams NM, Wood NW.
Journal: Lancet Neurol. 2016 Mar 23. [Epub ahead of print]
PMID: 27017469

The researchers analysed the DNA of 9387 people with Parkinson’s disease and 13 863 controls. They identified eight unrelated people with Parkinson’s disease who carried the chromosome 22q11.2 deletions. None of the controls had any of these deletions. Those people with Parkinson’s disease who had chromosome 22q11.2 deletions had earlier ages of onset (average age of diagnosis = 41 years old) than people with Parkinson’s disease who did not have the deletions (average age of diagnosis = 60.3 years). The researchers concluded that chromosome 22q11.2 deletions are associated with early onset Parkinson’s disease.

Some concluding thoughts

While the results of the Lancet Neurology study are very interesting, there are several important aspects to consider.

Firstly, the researchers noted that the estimated prevalence of 22q11.2 deletion syndrome in the general population is 0·024% or 24 in every 100,000 people. More importantly, as the study indicated the frequency of a 22q deletion among people with early-onset Parkinson’s disease is also very low (0·49% or 5 in every 1000 people with early-onset Parkinson’s disease). In fact, the number of people with the 22q11.2 deletion syndrome mutation and Parkinson’s disease is less than 20. So obviously this is a very low frequency event.

It is also interesting to consider that only 3% of patients with 22q11.2 deletion syndrome go on to develop Parkinson’s disease. Also a low frequency event. But studying this small population of people with a very specific genetic circumstance may enlighten us to some of the biological mechanisms causing this low frequency occurrence. And that may further aid us in better understanding other forms of Parkinson’s disease.

And that really is the take home message from this study:  we are gradually building a map of the connections between genetics and Parkinson’s disease, and while genetics will not explain every case of this condition, the knowledge we gain from this process will allow us to better target the disease in the long run.