Tagged: Lrrk2

AdoCbl + LRRK2 = modulation

 

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?

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The Parkinson’s Nebula?

 

There is a great deal of interest in genetic risk factors in Parkinson’s at the moment. A number of companies are providing direct-to-consumer services which provide individuals with some information about their family history and whether they have any of the more common genetic variations that are associated with medical conditions, like Parkinson’s.

Recently a new genetic data company has started – called Nebula Genomics – and they are offering a slightly different kind of service.

While many of the direct-to-consumer genetic companies have a business model that involves selling on genetic information to third parties, Nebula is offering a more patient-empowering option.

In today’s post, we will discuss the genetics of Parkinson’s, what Nebula Genomics is offering, and how this new service could be useful for the Parkinson’s community.

 


Prof George Church. Source: Biospace

Professor George Church is a person most readers will have never heard of.

He is the Robert Winthrop Professor of Genetics at Harvard Medical School and Professor of Health Sciences and Technology at Harvard and MIT, and was a founding member of the Wyss Institute for Biologically Inspired Engineering at Harvard.

He has co-author of over 500 academic papers, 143 patents and co-founded 22 biotech companies. In addition, he has participated in technology development, advising most of the major Genetic Sequencing companies, and he has been at the forefront of genetic research since the 1980s when he was involved with setting up the Human Genome Project.

His impact in the world of genetics has been tremendous.

But Prof Church is also something of a maverick. A left-field thinker. A disrupter.

He is a great supporter of open access genome sequencing and shareable human medical data. He is also keen to bring back extinct species, such as the Woolly Mammoth (Click here for more on this idea).

The return of the woolly mammoth. Source: Phys

Most recently, however, his name has been associated with a new company called Nebula Genomics.

What does Nebula Genomics do?

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Denali: Phase Ib clinical trial starts

 

Biotech firm Denali announced the dosing of the first person in their Phase Ib clinical study of their experimental treatment for Parkinson’s called DNL201.

DNL201 is an inhibitor of a Parkinson’s-associated protein called Leucine-rich repeat kinase 2 (LRRK2).

In Parkinson’s, there is evidence that LRRK2 is over activate, and by inhibiting LRRK2 Denali is hoping to slow the progression of Parkinson’s.

In today’s post, we will discuss what LRRK2 is, what evidence exists for DNL201, and what the new clinical trial will involve.

 


 

Founded in 2013, by a group of former Genentech executives, San Francisco-based Denali Therapeutics is a biotech company which is focused on developing novel therapies for people suffering from neurodegenerative diseases. Although they have product development programs for other condition (such as Amyotrophic Lateral Sclerosis and Alzheimer’s disease), Parkinson’s is their primary interest.

And their target for therapeutic effect?

The Parkinson’s-associated protein called Leucine-rich repeat kinase 2 (or LRRK2).

What is LRRK2?

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A Lewy body condition?

 

Lewy bodies are densely packed, circular clusters of protein that have traditionally been considered a characteristic feature of the Parkinsonian brain. Recently, however, evidence has been accumulating which calls into question this ‘defining feature’ of the condition.

The presence Lewy bodies in some cases of other neurological conditions (such as Alzheimer’s), and their complete absence in some cases of Parkinson’s, are leading many researchers to question their pivotal role in PD.

In today’s post, we will look at a new research report of Parkinson’s post mortem cases studies which present no Lewy bodies, and we will disucss what this might mean for our understanding of Parkinson’s and the future treatment of the condition.

 


Neuropathologists conducting a gross examination of a brain. Source: NBC

At present, a definitive diagnosis of Parkinson’s can only be made at the postmortem stage with an examination of the brain. Until that moment, all cases of Parkinson’s are ‘suspected’. When a neuropathologist makes an examination of the brain of a person who passed away with the clinical features of Parkinson’s, there are two characteristic hallmarks that they will be looking for in order to provide a final diagnosis of the condition:

1.  The loss of specific populations of cells in the brain, such as the dopamine producing neurons in a region called the substantia nigra, which lies in an area called the midbrain (at the base of the brain/top of the brain stem). As the name suggests, the substantia nigra region is visible due to the production of a ‘substance dark’ molecule called neuromelanin in the dopamine neurons. And as you can see in the image below, the Parkinsonian brain has less dark pigmented cells in the substantia nigra region of the midbrain.

The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinsonian brain (right). Source:Memorangapp

2.  Dense, circular clusters (or aggregates) of protein within cells, which are called Lewy bodies.

shutterstock_227273575A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news

A Lewy body is referred to as a cellular inclusion, as they are almost always found inside the cell body. They generally measure between 5–25 microns in diameter (5 microns is 0.005 mm) and thus they are tiny. But when compared to the neuron within which they reside they are rather large (neurons usually measures 40-100 microns in diameter).

A photo of a Lewy body inside of a neuron. Source: Neuropathology-web

Do all Parkinson’s brains have Lewy bodies?

This is a really interesting question. Welcome to the topic of this post.

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New LRRK2 results: Game changer?

 

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.

 


sergey_brin

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?

Continue reading

Two birds, one stone?

This week interesting research was published in the journal EMBO that looked at the Parkinson’s-associated protein Leucine-rich repeat kinase 2 (or LRRK2).

In their study, the researchers discovered that lowering levels of LRRK2 protein (in cells and animals) affected the ability of Mycobacterium tuberculosis – the bacteria that causes Tuberculosis – to replicate.

In today’s post, we will discuss what Tuberculosis is, how it relates to LRRK2 and Parkinson’s, and we will consider why this is potentially REALLY big news for Parkinson’s.


Daedalus and Icarus. Source: Skytamer

In Greek Mythology, there is the tale of Daedalus and Icarus.

Daedalus was a really smart guy, who designed the labyrinth on Crete, which housed the Minotaur (the ‘part man, part bull’ beast). For all his hard work, however, Daedalus was shut up in a tower and held captive by King Minos to stop the knowledge of his Labyrinth from spreading to the general public.

Source: Clansofhonor

But a mere tower was never going to stop Daedalus, and he set about fabricating wings for himself and his young son Icarus (who was also a captive).

Being stuck in the tower limited Daedalus’ access to feathers for making those wings, except of course for the large birds of prey that circled the tower awaiting the demise of Daedalus and his son. But he devised a clever way of throwing stones at the birds in such a way, that he is able to strike one bird and then the ricochet would hit a second bird.

And thus, the phase ‘killing two birds with one stone’ was born (or so it is said – there is also a Chinese origin for the phrase – Source).

Interesting. And this relates to Parkinson’s how?!?

Well, this week researchers in the UK have discovered that a protein associated with Parkinson’s is apparently also associated with another condition: Tuberculosis. And they also found that treatments being designed to target this protein in Parkinson’s, could also be used to fight Tuberculosis.

Two birds, one stone.

What is Tuberculosis?

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IBD+TNF AB ≠ PD?

The cryptic title of this post will hopefully make sense by the time you have finished reading the material present here.

This week, new research from the USA points towards an increased risk of Parkinson’s (PD) for people that suffer from inflammatory bowel disease (IBD). 

That same research, however, also points towards a clinically available treatment that appears to reduce the risk of Parkinson’s in individuals affected by inflammatory bowel disease. That treatment being: anti–tumor necrosis factor antibodies (TNF AB). Is that title making sense yet? If not, read on.

In today’s post, we will outline what inflammatory bowel disease is, review what the new research found, and discuss what is known about TNF in Parkinson’s. 


Inflammatory bowel disease. Source: Symprove

Inflammatory bowel disease (or IBD) is one of these umbrella terms that is used to refer to a group of inflammatory conditions of the large and small intestine:

The large and small intestine. Source: Adam

The symptoms of IBD can include abdominal pain, diarrhoea, vomiting, rectal bleeding, severe internal cramps/muscle spasms in the region of the pelvis, and weight loss.

The most common forms of IBD are Crohn’s disease and ulcerative colitis.

There has been an increased incidence of IBD since World War II, which could be associated with increased awareness and reporting of the condition, but it could also be linked with increases in meat consumption (Click here to read more about this). For example, in 2015, an estimated 1.3% of U.S. adults (3 million) were diagnosed with IBD, which was a large increase on the levels in 1999 (0.9% or 2 million adults – Source: CDC).

This is delightful, but what does it have to do with Parkinson’s?

So this week, an interesting study was published on the Journal of the American Medical Association – Neurology edition website:

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“What’s the evolutionary advantage of Parkinson’s?”

Each year King’s College London holds the Edmond J. Safra Memorial Lecture. It is a public event – exploring cutting-edge research on Parkinson’s – held in honour of the late philanthropist and financier, Mr Edmond J Safra, .

I was lucky enough to attend this year’s event (entitled A vision of tomorrow: How can technology improve diagnosis and treatment for Parkinson’s patients?). It highlighted the fantastic research being carried out by Professor Marios Politis and his team.

During the Q&A session of the event though, a question was asked from the audience regarding what the evolutionary advantage of Parkinson’s might be. The question drew a polite chuckle from the audience.

But the question wasn’t actually as silly as some might think.

In today’s post we look at some evidence suggesting an evolutionary advantage involving Parkinson’s.


King’s College London Chapel. Source: Schoolapply

Despite the impressive name, King’s College London is not one of the grand old universities of England.

Named after its patron King George IV (1762-1830), the university was only founded in 1829 (compare this with 1096 for Oxford and 1209 for Cambridge; even silly little universities like Harvard date back further – 1636). The university is spread over five separate campuses, geographically spread across London. But if you ever get the chance to visit the main Strand campus, ask for the chapel and take a moment to have a look – it is very impressive (the image above really doesn’t do it justice).

As I mentioned in the intro, each year King’s College London holds the Edmond J. Safra Memorial Lecture. It is an event that is open to the public and it involves a discussion regarding innovative new research on Parkinson’s. The evening is held in honour of the late Mr Edmond J Safra.

Edmond J. Safra. Source: Edmondjsafrafoundation

This year, Professor Marios Politis and members of his research group were presenting lectures on “How can technology improve diagnosis and treatment for Parkinson’s”. The lectures were very interesting, but the reason I am writing about it here is because during the question and answer session at the end of the lectures, the following question was asked:

“What’s the evolutionary advantage of Parkinson’s?”

Given the debilitating features of the condition, the audience was naturally amused by the question. And there was most likely several people present who would have thought the idea of any evolutionary advantage to Parkinson’s a ridiculous concept.

But it’s not.

And there is actually research to suggest that something evolutionary could be happening with Parkinson’s.

?!?!? What do you mean?

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Reduce your RAGE as you AGE

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 conditionsAGEs 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?

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Monthly Research Review – January 2018

Today’s (experimental) post provides something new – an overview of some of the major bits of Parkinson’s-related research that were made available in January 2018.


In January of 2018, the world was rocked by news that New Zealand had become the 11th country in the world to put a rocket into orbit (no really, I’m serious. Not kidding here – Click here to read more). Firmly cementing their place in the rankings of world superpowers. In addition, they became only the second country to have a prime minister get pregnant during their term in office (in this case just 3 months into her term in office – Click here to read more about this).

A happy New Zealand prime minister Jacinda Ardine

In major research news, NASA and NOAA announced that 2017 was the hottest year on record globally (without an El Niño), and among the top three hottest years overall (Click here for more on this), and scientists in China reported in the journal Cell that they had created the first monkey clones, named Zhong Zhong and Hua Hua (Click here for that news)

Zhong Zhong the cute little clone. Source: BBC

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