Tagged: Lrrk2

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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A.S.A.P

 

 

 

Yesterday the Aligning Science Across Parkinson’s (ASAP) initiative published a point of view in the scientific journal eLife. It laid out the objectives, themes and philosophy of an enormous new scientific effort to better understand Parkinson’s.

The overall project is being led by a Nobel prize winner scientist and employing the considerable resources of a very wealthy family that has been affected by Parkinson’s.

In today’s post we will have a look at what the ASAP initiative is planning to do and how it will hopefully significantly enhance our understanding of Parkinson’s.

 


Google co-founder Sergey Brin. Source: Emaze

Every so often something comes along that is so ‘next level’ in its scale and ambition that it gives you pause.

Two years ago, key Parkinson’s researchers from around the world were invited to the Milken Institute Center in for a grand meeting that was organised to plan out the foundations of a major new Parkinson’s research program that was to be called Aligning Science Across Parkinson’s (or ASAP).

The event was organised by Google co-founder Sergey Brin and his family foundation. The Brin family have been affected by Parkinson’s (Sergey’s mother and aunt both have the condition, and Sergey has a genetic risk factor that increases his risk of developing Parkinson’s).

The Brin Family – Sergey and his mother on the right. Source: CS

Sergey and his mother both carry a genetic variation in a region of DNA called PARK8. It is also known as Leucine-rich repeat kinase 2 (or simply LRRK2 – pronounced ‘lark 2’). The variant increases the risk of developing an young-onset, slow progressing form of Parkinson’s (Click here to read more about LRRK2). Sergey may never develop the condition, but he has decided not to take any chances. He has taken out an “insurance policy” by investing hundreds of millions of dollars into Parkinson’s research.

Part of that insurance policy is the ASAP effort.

And ASAP is being coordinated by Prof Randy Schekman.

Who is Prof Randy Schekman?
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Making sense of antisense

 

Recent regulator approvals and exciting new preclinical data has refocused attention on a treatment approach for genetic conditions that has travelled a long and winding road towards clinical use.

Antisense oligonucleotides represent a method of altering protein levels at the post transcriptional level – it basically stops certain RNAs from being translated into protein.

And recently, a new clinical trial has been registered which will explore the use of this treatment approach in people with Parkinson’s.

In today’s post, we will look at what antisense oligonucleotides are, how they work, what research has been conducted in the context of Parkinson’s, and some of the limitations of this approach that still exist.

 


Source: Youtube

Spinal muscular atrophy (or SMA) is a genetic disorder that results in the degeneration of motor neurons in the spinal cord. This leads to progressive weakening and atrophy of muscules, ultimately leaving sufferers paralysed. It is caused by loss-of-function mutations in the survival motor neuron 1 (SMN1) gene.

It is a terrible condition that starts in very young children and has an incidence approaching 1:10,000 live births.

Luckily, novel therapies are being developed to deal with this condition, and in 2016, the US FDA approved a new treatment – following rather dramatic clinical trial results – called Nusinersen. This new therapy has caused a great deal of excitement as it basically halted the progression of SMA in many cases.

And a recent long term report highlights some of these very impressive results:

Title: Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies.
Authors: Darras BT, Chiriboga CA, Iannaccone ST, Swoboda KJ, Montes J, Mignon L, Xia S, Bennett CF, Bishop KM, Shefner JM, Green AM, Sun P, Bhan I, Gheuens S, Schneider E, Farwell W, De Vivo DC; ISIS-396443-CS2/ISIS-396443-CS12 Study Groups.
Journal: Neurology. 2019 May 21;92(21):e2492-e2506.
PMID: 31019106                (This report is OPEN ACCESS if you would like to read it)

Most importantly, Nusinersen is having real impact on the children who are affected by this condition:

Interesting, but what exactly is Nusinersen?

It is an antisense oligonucleotide.

What are antisense oligonucleotides?

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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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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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