Tagged: Leucine-rich repeat kinase 2

The Lords of LRRK

 

Here on the SoPD we have discussed the Parkinson’s-associated protein LRRK2 many times. And we look forward to seeing the results of ongoing clinical trials of LRRK2 inhibitors.

But there are significant efforts ongoing to develop therapies that can indirectly target dysfunctional LRRK2 pathways (which may help avoid any potential side effects of direct inhibition)

Recently, researchers in Scotland and California have published research highlighting one such indriect approach to modulating LRRK2.

In today’s post, we will discuss what LRRK2 is, review the new data, and consider the ‘what happens next?’ question.

 


Prof Dario Alessi. Source: Eureka

Whenever I read a new research report about the activity of the Parkinson’s-associated protein, LRRK2, my first thought is usually “I wonder what Dario thinks of this?”

And I am not alone in this thought.

Prof Dario Alessi – Director of the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit and Professor of Signal Transduction, at the School of Life Sciences, University of Dundee – is widely recognised as one of the leading experts on the research of this particular protein.

University of Dundee. Source: Dundee

His thoughts/opinions are widely sought by many in the field – both academic and industry researchers.

And recently his lab – in collaboration with researchers are Stanford University – published a really interesting new report which we will discuss in today’s post.

But first, the obvious question:

What is LRRK2?

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ROPAD + LIPAD = NOT BAD :)

 

 

 

Approximately 10-20% of Parkinson’s cases are associated with a genetic risk factor which raises the chances of developing the condition.

Tremendous efforts are being made to not only better understand the underlying biology of these associations, but also to identify individuals who may be affected and invite them to take part in innovative new clinical trials.

The challenge is significant, however, as some genetic risk factors only affect less than 1% of the Parkinson’s community, meaning that hundreds of individuals must be genetically screened in order to identify 1 or 2 who might be eligible to take part in any subsequent study.

In today’s post, we will look at one such project (called the “Rostock International Parkinson’s Disease” (or ROPAD) study, and how it is helping to facilitate a second effort called the “LRRK2 International Parkinson’s Disease” (or LIPAD) project.

 


Rostock: Source: Lerbs

With 200,000+ inhabitants, Rostock was the third largest coastal city in Germany (after Kiel and Lübeck). The city lies on the estuary of the River Warnow in the Bay of Mecklenburg.

Each year, during the second weekend in August, Rostock holds one of the largest yachting events in the world: The Hanse Sail. It is a maritime celebration which attracts more than a million visitors and traditional sailing boats from all over the world.

Source: Hansetag-rostock

Rostock is also home to a company called Centogene.

What does Centogene do?

In 2006, neurologist Arndt Rolfs wanted to speed up the diagnosis of rare diseases. To do this, he founded Centogene. The company now has more than 300 employees and has built up one of the world’s largest data repository for genetic information on rare hereditary diseases. It sells genetic testing products and helps pharmaceutical firms develop new drugs for rare conditions.

It is also an instrumental part of a new Parkinson’s research project called ROPAD.

What is ROPAD?

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The Tau of LRRK2

 

Dense spherical clusters of a protein – called Lewy bodies – are one of the classical hallmarks of the Parkinsonian brain. They are a common pathological feature, but curiously they are not present in all cases of Parkinson’s.

For example, some individuals with certain forms of Parkinson’s associated with specific genetic mutations do not exhibit any Lewy bodies. Variations in a region of DNA called LRRK2 will increase one’s risk of developing Parkinson’s, but many of those who go on to develop LRRK2-associated Parkinson’s will have a complete absence of Lewy bodies in their brains. These cases have represented an enigma for the Parkinson’s research community and have been difficult to reconcile.

Recently, however, researchers from the University of Pennsylvania have reported a different kind of protein clustering in these LRRK2-associated cases with “no Lewy bodies”. The accumulating protein is called Tau.

In today’s post, we will look at what Tau is, review what the new research report found, and discuss what this discovery could potentially mean for the future treatment of Parkinson’s.

 


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?

Funnily enough, no.

And this is where the wheels fall off the wagon in our understanding (and ‘definitive’ definition) of Parkinson’s.

What do you mean?

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Something LRRKing in the immune system

 

 

Canadian scientists recently reported that mice with a specific genetic variation – in the Parkinson’s-associated LRRK2 gene – differ in how they are able to deal with bacterial and viral infections.

Curiously, mice with the Parkinson’s-associated LRRK2 mutation could handle a bacterial infection better than normal mice, while mice with no LRRK2 protein struggled against the infection. And the researchers found that this effect was most prominent in female mice in particular.

And curiously, when the mice are infected with a dangerous virus, female mice with the Parkinson’s-associated LRRK2 mutation fared worse than their male counterparts.

In today’s post, we will discuss what LRRK2 is, review the new research, and explore what the sex difference could mean in terms of Parkinson’s.

 


Autumn colours. Source: Visitsunlimited

I am a big fan of Autumn.

The colours and the crisp/bracing air. I love the long, slow afternoon strolls and anticipation of the festive season to come.

But most of all I love the license to eat all the good wintery food. After a summer of salads and light food, there is nothing better that entering a warm cottage or pub, and smelling the hearty food (my wife if French – we navigate based on the quality of eateries).

Autumn bliss. Source: Askdrake

But there is a down side to autumn: The start of the flu season.

Luckily, our immune systems are pretty robust – doing battle on a moment-to-moment basis with all manner of pathogenic agents.

Recently, some Canadian scientists discovered something interesing about the immune system and it relates to Parkinson’s.

What did they find?

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When miro just can’t let go

 

Stanford University researchers have recently published an interesting report in which they not only propose a novel biomarker for Parkinson’s, but also provide some compelling data for a novel therapeutic approach.

Their research focuses on a protein called Miro, which is involved in the removal of old or faulty mitochondria. Mitochondria are the power stations of each cells, providing cells with the energy they require to do what they do.

Specifically, the researchers found that Miro refuses to let go of mitochndria in people with Parkinson’s (which could act as a biomarker for the condition). They also found that pharmacologically forcing Miro to let go, resulted in neuroprotective benefits in models of Parkinson’s

In today’s post, we will discuss what Miro is, what the results of the new research suggest, and we will consider what will happen next.

 


 

Source: Amazingaccelerators

Every now and then a research report comes along and you think: “Whoa, that’s amazing!”

It a piece of work that breaks down your cynicism (which you have proudly built up over years of failed experiments) and disciplined scepticism (a critical ingredient for a career in scientific research – mantra: ‘question everything’). And for a moment you are taken in by the remarkable beauty of not just good research, but biology itself.

A couple of weeks ago, one such research report was published.

This is it here:

Title: Miro1 Marks Parkinson’s Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson’s Models.
Authors: Hsieh CH, Li L, Vanhauwaert R, Nguyen KT, Davis MD, Bu G, Wszolek ZK, Wang X.
Journal: Cell Metab. 2019 Sep 23. [Epub ahead of print]
PMID: 31564441

It’s a really interesting study for several reasons.

So what did they report?

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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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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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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

Inhibiting LRRK2: The Denali Phase I results

Denali

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.


Wonder_Lake_and_Denali

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.

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The LRRK Ascending

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.

sergey_brin

Nice guy.

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.

Continue reading