Approximately 1 person with Parkinson’s in every 100 will have a genetic variation in a specific section of their DNA that is referred to as LRRK2 – pronounced ‘lark 2’. The variation results in changes to the activity of the LRRK2 protein, and these changes are suspected of influencing the course of LRRK2-associated Parkinson’s.
Numerous biotech companies are now developing LRRK2 targetting agents that will modulate the activity of the LRRK2 protein.
Recently, however, a research report was published which points towards a potentially accessible method of LRRK2 modulation – one of the active forms of vitamin B12 – and if this research can be independently replicated, it may provide certain members of the Parkinson’s community with another means of dealing with the condition.
In today’s post, we will look at what LRRK2 is, review the new research, and discuss what could happen next.
This is Sergey Brin.
You may have heard of him – he was one of the founders of a small company called “Google”. Apparently it does something internet related.
Having made his fortune changing the way we find stuff, he is now turning his attention to other projects.
One of those other projects is close to our hearts: Parkinson’s.
Why is he interested in Parkinson’s?
In 1996, Sergey’s mother started experiencing numbness in her hands. Initially it was believed to be a bit of RSI (Repetitive strain injury). But then her left leg started to drag. In 1999, following a series of tests and clinical assessments, Sergey’s mother was diagnosed with Parkinson’s.
The Brin Family – Sergey and his mother on the right. Source: CS
It was not the first time the family had been affected by the condition – Sergey’s late aunt had also had Parkinson’s.
Given this coincidental family history of this particular condition, both Sergey and his mother decided to have their DNA scanned for any genetic errors (also called ‘variants’ or ‘mutations’) that are associated with an increased risk of developing Parkinson’s. And they discovered that they were both carrying a genetic variation in a gene (a section of DNA that provides the instructions for making a protein) called PARK8 – one of the Parkinson’s-associated genes (Click here to read more about the genetics of Parkinson’s and the PARK genes).
The PARK8 gene is also known as Leucine-rich repeat kinase 2 (or LRRK2 – pronounced ‘lark 2’).
What is LRRK2?
Millions of dollars in research funding for Parkinson’s has been poured into the biology and function of just one hyperactive protein. It is called Leucine-rich repeat kinase 2 (or LRRK2). Genetic mutations in the gene that gives rise to this abnormal version of the protein can leave carriers with a higher risk of developing Parkinson’s.
All of that research funding has resulted in an incredible leap forward in our understanding of LRRK2, which has further led to clinical trials focused solely on LRRK2. Mutations in the LRRK2 gene occur in only 1-2% of the Parkinson’s population, however, which has led to some complaints that too much research is being focused on only a small fraction of the people affected by PD.
New research published this week could silence those complaints.
In today’s post we will discuss a new report suggesting that independent of any genetic mutations, LRRK2 may actually play a role in idiopathic (or spontaneous) forms of Parkinson’s, which means that the treatments being developed for LRRK2 could be beneficial for a wider section of the PD community.
This is Sergey Brin.
He’s a dude.
You may have hear of him – he was one of the founders of a small company called “Google”.
Having changed the way the world searches the internet, he is now turning his attention to other projects.
One of those other projects is close to our hearts: Parkinson’s.
Why is he interested in Parkinson’s?
An Advanced Glycation Endproduct (or AGE) is a protein or lipid that has become glycated.
Glycation is a haphazard process that impairs the normal functioning of molecules. It occurs as a result of exposure to high amounts of sugar. These AGEs are present at above average levels in people with diabetes and various ageing-related disorders, including neurodegenerative conditions. AGEs have been shown to trigger signalling pathways within cells that are associated with both oxidative stress and inflammation, but also cell death.
RAGE (or receptor of AGEs) is a molecule in a cell membrane that becomes activated when it interacts with various AGEs. And this interaction mediates AGE-associated toxicity issues. Recently researchers found that that neurons carrying the Parkinson’s associated LRRK2 G2019S genetic variant are more sensitive to AGEs than neurons without the genetic variant.
In today’s post we will look at what AGE and RAGE are, review the new LRRK2 research, and discuss how blocking RAGE could represent a future therapeutic approach for treating Parkinson’s.
The wonder of ageing. Source: Club-cleo
NOTE: Be warned, the reading of this post may get a bit confusing. We are going to be discussing ageing (as in the body getting old) as well as AGEing (the haphazard process processing of glycation). For better clarification, lower caps ‘age’ will refer to getting old, while capitalised ‘AGE’ will deal with that glycation process. I hope this helps.
Ageing means different things to different people.
For some people ageing means more years to add to your life and less activity. For others it means more medication and less hair. More wrinkles and less independence; more arthritis and less dignity; More candles, and less respect from that unruly younger generation; More… what’s that word I’m thinking of? (forgetfulness)… and what were we actually talking about?
Wisdom is supposed to come with age, but as the comedian/entertainer George Carlin once said “Age is a hell of a price to pay for wisdom”. I have to say though, that if I had ever met Mr Carlin, I would have suggested to him that I’m feeling rather ripped off!
George Carlin. Source: Thethornycroftdiatribe
Whether we like it or not, from the moment you are born, ageing is an inevitable part of our life. But this has not stopped some adventurous scientific souls from trying to understand the process, and even try to alter it in an attempt to help humans live longer.
Regardless of whether you agree with the idea of humans living longer than their specified use-by-date, some of this ageing-related research could have tremendous benefits for neurodegenerative conditions, like Parkinson’s.
What do we know about the biology of ageing?
This week Denali Therapeutics released the results of a phase I clinical trial of their primary product, called DNL-201.
DNL-201 is a LRRK2 inhibitor that the company is attempting to take to the clinic for Parkinson’s disease.
In today’s post we will look at what LRRK2 is, how an inhibitor might help in Parkinson’s, and what the results of the trial actually mean.
Denali. Source: Wikipedia
Denali (Koyukon for “the high one”; also known as Mount McKinley) in Alaska is the highest mountain peak in North America, with a summit elevation of 20,310 feet (6,190 m) above sea level. The first verified ascent to Denali’s summit occurred on June 7, 1913, by four climbers Hudson Stuck, Harry Karstens, Walter Harper, and Robert Tatum.
Tatum (left), Karstens (middle), and Harper (right). Source: Gutenberg
Robert Tatum later commented, “The view from the top of Mount McKinley is like looking out the windows of Heaven!”
More recently another adventurous group associated with ‘Denali’ have been trying to scale lofty heights, but of a completely different sort from the mountaineering kind.
Genetic mutations (or ‘variants’) in the Leucine-rich repeat kinase 2 (or LRRK2; also known as Dardarin) gene are associated with increased risk of Parkinson’s. As a result this gene has become the focus of a lot of genetic research.
But what about LRRK2’s less well-known, rather neglected sibling LRRK1?
In today’s post, we will look at new research that suggests the LRRK siblings could both be involved with Parkinson’s disease.
I recommend to the reader that today’s post should be read with the following music playing in the background:
Inspired by a poem of the same title, English composer Ralph Vaughan Williams wrote ‘The Lark Ascending’ in 1914. It is still to this day, a tune that remains a firm favourite with BBC listeners here in the UK (Source).
On to business:
While the music and the poem are about a songbird, today’s SoPD post deals with a different kind of Lark.
Or should I say LRRK.
This is Sergey Brin.
He was one of the founders of a small company you may have heard of – it’s called “Google”.
Having changed the way the world searches the internet, he is now turning his attention to other projects.
One of those other projects is close to our hearts: Parkinson’s disease.
We have previously discussed the powerful antioxidant Resveratrol, and reviewed the research suggesting that it could be beneficial in the context of Parkinson’s disease (Click here to read that post).
I have subsequently been asked by several readers to provide a critique of the Parkinson’s-associated research focused on Resveratrol’s twin sister, Pterostilbene (pronounced ‘Terra-still-bean’).
But quite frankly, I can’t.
Why? Because there is NO peer-reviewed scientific research on Pterostilbene in models of Parkinson’s disease.
In today’s post we will look at what Pterostilbene is, what is known about it, and why we should seriously consider doing some research on this compound (and its cousin Piceatannol) in the context of Parkinson’s disease.
Blue berries are the best natural source of Pterostilbene. Source: Pennington
So this is likely to be the shortest post in SoPD history.
Because there is nothing to talk about.
There is simply no Parkinson’s-related research on the topic of today’s post: Pterostilbene. And that is actually a crying shame, because it is a very interesting compound.
What is Pterostilbene?
Like Resveratrol, Pterostilbene is a stilbenoid.
Stilbenoids are a large class of compounds that share the basic chemical structure of C6-C2-C6:
Resveratrol is a good example of a stilbenoid. Source: Wikipedia
Stilbenoids are phytoalexins (think: plant antibiotics) produced naturally by numerous plants. They are small compounds that become active when the plant is under attack by pathogens, such as bacteria or fungi. Thus, their function is generally considered to part of an anti-microbial/anti-bacterial plant defence system for plants.
The most well-known stilbenoid is resveratrol which grabbed the attention of the research community in a 1997 study when it was found to inhibit tumour growth in particular animal models of cancer:
Last Monday, a SpaceX rocket lifted off from the Florida peninsular on route to the International Space Station.
On board that craft was an experiment that could have big implications for Parkinson’s disease. It involves a Parkinson’s-associated protein called Leucine-rich repeat kinase 2 (or LRRK2).
In today’s post, we will discuss why we needed to send this protein into orbit.
The International Space Station. Source: NASA
When you look up at the sky tonight – if you look for long enough – you may well see a bright little object hurtling across the sky (Click here to learn more about how to track the International Space Station). Know that inside that bright little object passing over you there is currently some Parkinson’s disease-related research being conducted.
What is the International Space Station?
The International Space Station (or the ISS) is the largest human-made object that we have ever put into space. It is so big in fact that you can see it with the naked eye from Earth.
(How’s that for exciting viewing?)
The current space station is 73.3 metres (240 feet) long and 44.5 metres (146 feet) wide, weighing approximately 420 tonnes (924,740 lb), and it has been continuously occupied for 16 years and 289 days, making it the longest continuous human presence in low Earth orbit. The ISS travels at a speed of 7.67 km/second, maintains an altitude of between 330 and 435 km (205 and 270 mi), and completes 15.54 orbits per day (it has made over 102,000 orbits!).
The size of the the ISS compared to a Boeing Jumbo jet. Source: Reddit
First approved by President Ronald Reagan in 1984, it was not until November 1998 that the first components of the International space station were first launched into orbit. 36 shuttle flights were made to help build the station. The first crew members took up residence on the 2nd November 2000, and the station was completed in 2011. There is always 6 crew members on board – the current team are Expedition 52 – and it has been visited by 220 astronauts, cosmonauts and space tourists from 17 different nations since the project began.
Oh yeah, and if you want to see what it looks like on board the ISS, in 2015 the European Space Agency provided an interactive tour and earlier this year Google Maps added an interactive tour of the ISS.
In Silicon valley (California), everyone is always looking for the “next killer app” – the piece of software (or application) that is going to change the world. The revolutionary next step that will solve all of our problems.
The title of today’s post is a play on the words ‘killer app’, but the ‘app’ part doesn’t refer to the word application. Rather it relates to the Alzheimer’s disease-related protein Amyloid Precursor Protein (or APP). Recently new research has been published suggesting that APP is interacting with a Parkinson’s disease-related protein called Leucine-rich repeat kinase 2 (or LRRK2).
The outcome of that interaction can have negative consequences though.
In today’s post we will discuss what is known about both proteins, what the new research suggests and what it could mean for Parkinson’s disease.
Seattle. Source: Thousandwonders
In the mid 1980’s James Leverenz and Mark Sumi of the University of Washington School of Medicine (Seattle) made a curious observation.
After noting the high number of people with Alzheimer’s disease that often displayed some of the clinical features of Parkinson’s disease, they decided to examined the postmortem brains of 40 people who had passed away with pathologically confirmed Alzheimer’s disease – that is, an analysis of their brains confirmed that they had Alzheimer’s.
What the two researchers found shocked them:
Title: Parkinson’s disease in patients with Alzheimer’s disease.
Authors: Leverenz J, Sumi SM.
Journal: Arch Neurol. 1986 Jul;43(7):662-4.
Of the 40 Alzheimer’s disease brains that they looked at nearly half of them (18 cases) had either dopamine cell loss or Lewy bodies – the characteristic features of Parkinsonian brain – in a region called the substantia nigra (where the dopamine neurons are located). They next went back and reviewed the clinical records of these cases and found that rigidity, with or without tremor, had been reported in 13 of those patients. According to their analysis 11 of those patients had the pathologic changes that warranted a diagnosis of Parkinson’s disease.
And the most surprising aspect of this research report: Almost all of the follow up studies, conducted by independent investigators found exactly the same thing!
It is now generally agreed by neuropathologists (the folks who analyse sections of brain for a living) that 20% to 50% of cases of Alzheimer’s disease have the characteristic round, cellular inclusions that we call Lewy bodies which are typically associated with Parkinson disease. In fact, in one analysis of 145 Alzheimer’s brains, 88 (that is 60%!) had chemically verified Lewy bodies (Click here to read more about that study).
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
Oh, and if you are wondering whether this is just a one way street, the answer is “No sir, this phenomenon works both ways”: the features of the Alzheimer’s brain (such as the clustering of a protein called beta-amyloid) are also found in many cases of pathologically confirmed Parkinson’s disease (Click here and here to read more about this).
So what are you saying? Alzheimer’s and Parkinson’s disease are the same thing???
When people in England think of the city of Sheffield, quite often images of a great industrial past will come to mind.
They usually don’t think of the flies, fish and (yes) a Tigar (no, not a typo!) that are influencing Parkinson’s disease research in the city.
In today’s post we will look at how the re-invention of a city could have a major impact on Parkinson’s disease.
The industrial heritage of Sheffield. Source: SIMT
It is no under statement to say that the history of Sheffield – a city in South Yorkshire, England – is forged in steel.
In his 1724 book, “A tour thro’ the whole island of Great Britain“, the author Daniel Defoe wrote of Sheffield:
“Here they make all sorts of cutlery-ware, but especially that of edged-tools, knives, razors, axes, &. and nails; and here the only mill of the sort, which was in use in England for some time was set up, for turning their grindstones, though now ’tis grown more common”
Sheffield has a long history of metal work, thanks largely to its geology: The city is surrounded by fast-flowing rivers and hills containing many of the essential raw materials such as coal and iron ore.
And given this fortunate circumstance and an industrious culture, the city of Sheffield particularly prospered during the industrial revolution of the mid-late 1800s (as is evident from the population growth during that period).
The population of Sheffield over time. Source: Wikipedia
But traditional manufacturing in Sheffield (along with many other areas in the UK) declined during the 20th century and the city has been forced to re-invent itself in the early 21st century. And this time, rather than taking advantage of their physical assets, the city is focusing on its mental resources.
Great. Interesting stuff. Really. But what does this have to do with flies, fish and Parkinson’s disease???
Indeed. Let’s get down to business.
The Sheffield Institute for Translational Neuroscience (SITraN) was officially opened in 2010 by Her Majesty The Queen. It is the first European Institute purpose-built and dedicated to basic and clinical research into Motor Neuron Disease as well as related neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease.
Since its opening, the institute has published some pretty impressive research, particularly in the field of Parkinson’s disease.
And here is where we get to the flies:
Pink flies. Source: Wallpapersinhq
We have previously discussed “Pink” flies and their critical role in Parkinson’s research (Click here to read that post).
Today we are going to talk about Lrrk2 flies.
What is Lrrk2?
This is Sergey Brin.
He’s a dude.
One of the founders of the search engine company “Google”. Having changed the world, he is now turning his attention to other projects.
One of those other projects is close to our hearts: Parkinson’s disease.
In 1996, Sergey’s mother started experiencing numbness in her hands. Initially it was believed to be RSI (Repetitive strain injury). But then her left leg started to drag. In 1999, following a series of tests, Sergey’s mother was diagnosed with Parkinson’s disease. It was not the first time the family had been affected by the condition: Sergey’s late aunt had also had Parkinson’s disease.
Both Sergey and his mother have had their DNA scanned for mutations that increase the risk of Parkinson’s disease. And they discovered that they were both carrying a mutation on the 12th chromosome, in a gene called PARK8 – one of the Parkinson’s disease associated genes. Autosomal dominant mutations (meaning if you have just one copy of the mutated gene) in the PARK8 gene dramatically increase one’s risk of developing Parkinson’s disease.
PARK8 provides the instructions for making an enzyme called Leucine-rich repeat kinase 2 (or Lrrk2).
The structure of Lrrk2. Source: Wikipedia
Also known as ‘Dardarin‘ (from the Basque word “dardara” which means trembling), Lrrk2 has many functions within a cell – from helping to move things around inside the cell to helping to keep the power on (involved with mitochondrial function).
Now, not everyone with this particular mutation will go on to develop Parkinson’s disease, and Sergey has decided that his chances are 50:50. But he does not appear to be taking any chances though. Being one of the founders of a large company like Google, has left Sergey with considerable resources at his disposal. And he has chosen to focus some of those resources on Lrrk2 research (call it an insurance policy). He has done this via considerable donations to groups like the Michael J Fox foundation.
Actor Michael J Fox was diagnosed at age 30. Source: MJFox foundation
So just as Pink flies derive their name from mutations in the Parkinson’s associated Pink1 gene, Lrrk2 flies have mutations in the Lrrk2 gene.
So what have the researchers at Sheffield done with the Lrrk2 flies?
In 2013, the Sheffield researchers published an interesting research report:
Title: Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson’s disease
Authors: Mortiboys H, Aasly J, Bandmann O.
Journal: Brain. 2013 Oct;136(Pt 10):3038-50.
In this study, the investigators took 2000 drugs (including 1040 licensed drugs and 580 naturally occurring compounds) and conducted a massive screen to identify drugs that could rescue mitochondrial dysfunction in PARK2 (Parkin) mutant cells.
Mitochondria are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.
Mitochondria and their location in the cell. Source: NCBI
In certain genetic forms of Parkinson’s disease (such as those associated with mutations in the PARK2 gene), the mitochondria in cells becomes dysfunctional and may not be disposed of properly (Click here to read our previous post related to this).
In their huge screen of 2000 drugs, the researchers in Sheffield identified 15 drugs that could rescue the mitochondria dysfunction in the PARK2 skins cells. Of those 15 compounds, two were chosen for further functional studies. They were:
- Ursocholanic acid
- Dehydro(11,12)ursolic acid lactone
Neither ursocholanic acid nor dehydro(11,12)ursolic acid lactone are FDA-licensed drugs. We have little if any information regarding their use in humans. Given this situation, the researchers turned their attention to the chemically related bile acid ‘ursodeoxycholic acid’, which has been in clinical use for more than 30 years.
What is Ursodeoxycholic Acid?
Ursodeoxycholic Acid (or UDCA) is a drug that is used to to improve bile flow and reduce gallstone formation. In the USA it is also known as ‘ursodiol’.
Ursodiol. Source: Wikimedia
Bile is a fluid that is made and released by your liver, and it stored in the gallbladder. Its function is to help us with digestion. UDCA occurs naturally in bile – it is basically a bile acid and can therefore be useful in dissolving gallstones. UDCA has been licensed for the treatment of patients since 1980. UDCA also reduces cholesterol absorption.
So what did the Sheffield researchers find with UDCA?
The researchers tested UDCA on mitochondrial function in PARK2 skin cells, and they found that the drug rescued the cells. They then tested UDCA on skin cells from people with Parkinson’s disease who had mutations in the PARK8 (Lrrk2) gene (G2019S).
The researchers had previously found impaired mitochondrial function and morphology in skin cells taken from people with PARK8 associated Parkinson’s disease (Click here to read more about this), and other groups had reported similar findings (Click here for more on this).
And when they treated the Lrrk2 cells with UDCA, guess what happened?
UDCA was able to rescue the mitochondrial effect in those cells as well!
Obviously these results excited the Sheffield scientists and they set up a collaboration with researchers at York University and from Norway, to look at the potential of UDCA in rescuing the fate of Lrrk2 flies. The results of that study were published two years ago:
Title: UDCA exerts beneficial effect on mitochondrial dysfunction in Lrrk2 (G2019S) carriers and in vivo.
Authors: Mortiboys H, Furmston R, Bronstad G, Aasly J, Elliott C, Bandmann O.
Journal: Neurology. 2015 Sep 8;85(10):846-52.
PMID: 26253449 (This article is OPEN ACCESS if you would like to read it).
The researchers tested UDCA on flies (or drosophila) with specific Lrrk2 mutations (G2019S) display a progressive loss of photoreceptor cell function in their eyes. The mitochondria in the photoreceptor are swollen and disorganised. When the investigators treated the flies with UDCA, they found approximately 70% rescue of the photoreceptor cells function.
The researchers in Sheffield concluded that UDCA has a marked rescue effect on cells from a Parkinson’s disease-associated gene mutation model, and they proposed that “mitochondrial rescue agents may be a promising novel strategy for disease-modifying therapy in Lrrk2-related PD, either given alone or in combination with Lrrk2 kinase inhibitors” (for more information about the Lrrk2 inhibitors they refer, click here).
And the good news regarding this line of research: other research groups have also observed similar beneficial effects with UDCA in models of Parkinson’s disease:
Title: Ursodeoxycholic acid suppresses mitochondria-dependent programmed cell death induced by sodium nitroprusside in SH-SY5Y cells.
Authors: Chun HS, Low WC.
Journal: Toxicology. 2012 Feb 26;292(2-3):105-12.
This research group also demonstrated that UDCA could reduce cell death in a cellular model of Parkinson’s disease.
And this study was followed by another one from a different research group, which involved testing UDCA in animals:
Title: Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations.
Authors: Abdelkader NF, Safar MM, Salem HA.
Title: Mol Neurobiol. 2016 Mar;53(2):810-7.
These researchers found UDCA rescued a rodent model of Parkinson’s disease (involving the neurotoxin rotenone). UDCA not only improved mitochondrial performance in the rats, but also demonstrated anti-inflammatory and anti-cell death properties.
Given all this research, the Sheffield researchers are now keen to test UDCA in clinical trials for Parkinson’s disease.
Has anyone tested UDCA in the clinic for Parkinson’s disease?
Not that we are aware of, but two groups are interested in attempting it.
Firstly, the University of Minnesota – Clinical and Translational Science Institute has registered a trial (Click here to read more about this). This trial will not, however, be testing efficacy of the drug on Parkinson’s symptoms. It will focus on measuring UDCA levels in individuals after four weeks of repeated high doses of oral UDCA (50mg/kg/day), and determining the bioenergetic profile and ATPase activity in those participants. Basically, they want to see if UDCA is safe and active in people with Parkinson’s disease.
EDITOR’S NOTE HERE: Before we move on, the team at the SoPD would like to say that while UDCA is a clinically available drug, it is still experimental for Parkinson’s disease. There is no indication yet that it has beneficial effects in people with Parkinson’s disease. In addition, UDCA is also is known to have side effects, which include flu symptoms, nausea, diarrhea, and back pain. And individuals have been known to have allergic reactions to UDCA treatment (Click here and here for more on the side effects of UDCA). Thus we must impress caution on anyone planning to experiment with this drug. Before attempting any kind of change in a current treatment regime, PLEASE discuss your plans with a medically qualified physician who is familiar with your case history.
Ok, so that was the flies research, what about the fish? And the… uh, tigar?
Yes. The fish are called Zebrafish (or Danio rerio).
They are a tropical freshwater fish that is widely used in biological research.
Biology researchers love these little guys because their genome has been fully sequenced and they has well characterised and testable behaviours. In addition, their development is very rapid (3 months), and its embryos are large and transparent.
And the researchers at Sheffield are using these fish to study Parkinson’s disease.
How did they do that?
Title: TigarB causes mitochondrial dysfunction and neuronal loss in Pink1 deficiency
Authors: Flinn LJ, Keatinge M, Bretaud S, Mortiboys H, Matsui H, De Felice E, Woodroof HI, Brown L, McTighe A, Soellner R, Allen CE, Heath PR, Milo M, Muqit MM, Reichert AS, Köster RW, Ingham PW, Bandmann O.
Journal: Ann Neurol. 2013 Dec;74(6):837-47.
PMID: 24027110 (This article is OPEN ACCESS if you would like to read it)
Firstly, the group at Sheffield generated zebrafish that had a mutation in the Parkinson’s associated gene ‘PARK6’. This gene provides the plans for the production of a protein called Pink1 (we have previously discussed Pink1 – click here to read more on this).
In normal healthy cells, the Pink1 protein is absorbed by mitochondria and eventually degraded as it is not used. In unhealthy cells, however, this process becomes inhibited and Pink1 starts to accumulate on the outer surface of the mitochondria. Sitting on the surface, it starts grabbing another Parkinson’s associated protein called Parkin. This pairing is a signal to the cell that this particular mitochondria is not healthy and needs to be removed.
Pink1 and Parkin in normal (right) and unhealthy (left) situations. Source: Hindawi
The process by which mitochondria are removed is called mitophagy. Mitophagy is part of the autophagy process, which is an absolutely essential function in a cell. Without autophagy, old proteins and mitochondria will pile up making the cell sick and eventually it dies. Through the process of autophagy, the cell can break down the old protein, clearing the way for fresh new proteins to do their job.
Think of autophagy as the waste disposal/recycling process of the cell.
The process of autophagy. Source: Wormbook
Waste material inside a cell is collected in membranes that form sacs (called vesicles). These vesicles then bind to another sac (called a lysosome) which contains enzymes that will breakdown and degrade the waste material. The degraded waste material can then be recycled or disposed of by spitting it out of the cell.
In the case of a PARK6 mutations, Pink1 protein can not function properly with Parkin and the autophagy process breaks down. As a result, the old or unhealthy mitochondria start to pile up in the cell, resulting in the cell getting sick and dying.
Now back to the Zebrafish.
When the Sheffield researchers mutated PARK6 in the zebrafish, they noticed that the fish had a very early and persistent loss of dopamine neurons in their brains. These fish also had enlarged, unhealthy mitochondria and reduced mitochondrial activity.
Given this result, the investigators next wanted to identify which genes have increased or decreased levels of activity as a result of this genetic manipulation. They identified 108 genes that were higher in the PARK6 mutant, and 146 genes had lower activity.
One gene in particular had activity levels 12 times higher in the PARK6 mutant fish than the normal zebrafish.
The name of that gene? TP53-Induced Glycolysis And Apoptosis Regulator (or Tigar).
What is Tigar?
Tigar is a gene that provides the instructions for making a protein that is activated by p53 (also known as TP53).
What does that mean?
p53 is a protein that has three major functions: controlling cell division, DNA repair, and apoptosis (or cell death). p53 performs these functions as a transcriptional activator (that is a protein that binds to DNA and helps produce RNA (the process of transcription) – see our previous post explaining this).
p53 protein structure, bound to DNA (in gold). Source: Wikipedia
In regulating the cell division, p53 prevents cells from dividing too much and in this role it is known as a tumour suppression – it suppresses the emergence of cancerous tumours. Genetic mutations in the p53 gene result in run away cell division, and (surprise!) as many as 50% of all human tumours contain mutations in the p53 gene.
Cancer vs no cancer. Source: Khan Academy
In DNA repair, p53 is sometimes called “the guardian of the genome” as it prevents mutations and helps to conserve stability in the genome. This function also serves to prevent the development of cancer, by helping to repair potentially cancer causing mutations….and in this role it is known as a tumour suppression. Obviously, if there is a mutation in the p53 gene, less DNA repair will occur – increasing the risk of cancer occurring.
And finally, in cell death, p53 plays a critical role in telling a cell when to die. And (continuing with the cancer theme), if there is a mutation in the p53 gene, fewer cells will be told to die – increasing the risk of cancer occurring. And in this role p53 is known as a tumour suppression.
In normal cells, the levels of p53 protein are usually low. When a cell suffers DNA damage and stress, there is often an increase in the amount of p53 protein. If this increases past a particular threshold, then the cell will be instructed to die.
If you haven’t guessed yet, p53 is a major player inside most cell, and it controls the activity of a lot of genes.
And one of those genes is Tigar.
But what does Tigar actually do?
So we have explained the “TP53-Induced” part of the “TP53-Induced Glycolysis And Apoptosis Regulator” name, let’s now focus on the “Glycolysis And Apoptosis Regulator”
Tigar is an interesting protein because it is an enzyme that primarily functions as a regulator of the breaking down of glucose (“Glycolysis” involves the conversion of glucose into a chemical called pyruvate). In addition to this role, however, Tigar acts in preventing cell death (or apoptosis).
Increased levels of Tigar protects cells from oxidative-stress induced apoptosis, by decreasing the levels of free radicals. In this way, it promotes anti-oxidant activities.
But hang on a second, anti-oxidant activity should be good for the cell right? Why are the dopamine cells are dying if Tigar levels are increasing in the PARK6 mutants?
The answer: TIGAR is also a negative regulator of a process called mitophagy. As we discussed above, mitophagy is the process of removing mitochondria by autophagy. Increases in the levels of TIGAR blocks mitophagy in a cell, and results in an increased number of swollen and unhealthy mitochondria in those cells (Click here to read more about this). These swollen mitochondria are comparable to the enlarged mitochondria identified the PARK6 zebrafish by the Sheffield researchers.
And the researchers believe that this may be the cause of the cell death in the PARK6 zebrafish – the double impact of PARK6 and Tigar induced problems with mitophagy.
NOTE: Problems with mitophagy is believed to be an important mechanism in the development of early-onset Parkinson’s disease (Click here for a recent review on this)
Ok, and what did the Sheffield researchers do next?
Given that there was such a huge increase in Tigar levels in the PARK6 zebrafish, the investigators decided to reduce Tigar levels in the PARK6 zebrafish to see what impact this would have on the fish (and their mitochondria).
Remarkably, reductions of Tigar levels resulted in complete rescue of the dopamine neurons in the PARK6 fish. It also increased mitochondrial activity in those cells, and reduced the activation of the microglia cells, which can also play a role in the removal of sick cells in the brain.
The researchers concluded that the results demonstrate that TIGAR is “a promising novel target for disease‐modifying therapy in Pink1‐related Parkinson’s disease”.
And what are the researchers planning to do next with Tigar?
Prof Oliver Bandmann, the senior scientist who ran the study, has said that they “need to finish studying TIGAR levels in the brains of people with Parkinson’s and want to better understand how this protein is involved in maintaining the cell batteries – called ‘mitochondria'” (Source).
Our guess is that the group will also be conducting studies looking at Tigar reduction in rodent models of Parkinson’s disease to determine if this is a viable target in mammals. If Tigar reduction in rodents is found to be effective, the researchers will probably turn their attention to drug screening studies to identify currently available drugs that can reduce the activity of Tigar. Such a drug would provide us with yet another potential treatment for Parkinson’s disease.
We’ll be keeping an eye out for these pieces of research.
This is all very interesting. What does the future hold for Parkinson’s research in Sheffield?
Well, in a word: Keapstone.
Source: Parkinson’s UK
The goal of the company – the first of its kind – is to combine world-leading research from the University with funding and expertise from the charity to help develop revolutionary drugs for Parkinson’s disease.
What is virtual about it? The biotech won’t be building its own labs, employing a team of specialist laboratory scientists, or buying any high-tech equipment (which would all be incredibly expensive). Rather they will form partnerships with groups that do specific tasks the best.
Here is a video of Dr Author Roach (director of Research at Parkinson’s UK) explaining the idea behind this endeavour:
By seeking a collaboration with Sheffield in the creation of a spin-out biotech company, Parkinson’s UK is not only acknowledging Sheffield’s track record, but also making an investment in their future research. While we cannot be entirely sure of what the long-term future holds for Parkinson’s research in Sheffield, we do know that Keapstone will be an important aspect of it in the immediate future.
Could this be a model for the future of Parkinson’s disease research? Only time will tell. We will have a closer look at Keapstone Therapeutics in an upcoming post.
Click here to learn more about the virtual biotech project.
So what does it all mean?
In 2017, we here at the SoPD have decided to begin highlighting some of the Parkinson’s disease research centres as an addition feature on the blog. We have not been approached by the research group in Sheffield or the University itself, and our selection of this city as our first case study was based purely on the fact that we really like what is happening there with regards to Parkinson’s research!
The research group in Sheffield has undertaken multiple lines of research which could potentially providing us with several novel treatment options for Parkinson’s disease. These lines of research have focused not only on clinically available drugs, but also identifying novel targets. We like what they are doing and will keep a close eye on progress there.
And over the next year we will select additional centres of Parkinson’s research based on the same criteria (us liking what they are doing). Our next case study will be the Van Andel Research Institute in Grand Rapids, Michigan (we would hate to be accused of having a UK bias).
EDITORIAL NOTE: Under absolutely no circumstances should anyone reading the material on this website consider it medical advice. The information provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. While some of the drugs discussed on this website are clinically available, they may have serious side effects. We urge caution and professional consultation before altering any treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.
The banner for today’s post was sourced from TotalProduceLocal