Tagged: Lrrk2

Too much LRRK2 begets too little GCase?

 

New research from multiple independent research groups proposes that one Parkinson’s associated protein (LRRK2) may be affecting the activity of another Parkinson’s associated protein (GCase).

Specifically, when LRRK2 becomes hyperactive (as is the situation in some cases of Parkinson’s), it causes is associated with a reduction in the amount of GCase activity.

In today’s post, we will discuss what LRRK2 and GCase both do, what the new research suggests, and how this news could influence efforts to treat Parkinson’s in the future.

         


Connections. Source: Philiphemme

For a long time, the Parkinson’s research community had a set of disconnected genetic risk factors – tiny errors in particular regions of DNA that were associated with an increased risk of developing Parkinson’s – but there seemed to be little in the way of common connections between them.

Known genetic associations with PD. Source: PMC

The researchers studied the biological pathways associated with these risk factors, trying to identify potential therapeutic angles as well as looking for connections between them.

The therapies are currently being clinically tested (Click here to read more about these), but the connections have taken a lot longer to find.

Recently one important connection has been identified by several research groups and it could have important implications for how Parkinson’s will be treated in the future.

What’s the connection?

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The road ahead: 2020

Here at the SoPD, we are primarily interested in disease modification for Parkinson’s. While there is a great deal of interesting research exploring the causes of the condition, novel symptomatic therapies, and other aspects of Parkinson’s, my focus is generally on the science seeking to slow, stop or reverse the condition.

At the start of each year, it is a useful practise to layout what is planned and what we will be looking for over the next 12 months. Obviously, where 2020 will actually end is unpredictable, but an outline of what is scheduled over the next year will hopefully provide us with a useful resource for better managing expectations.

In this post, I will try to lay out some of what 2020 holds for us with regards to clinical research focused on disease modification for Parkinson’s.


BP

Lord Robert Baden-Powell. Source: Utahscouts

My old scout master once looked around our horse shoe, making eye contact with each of us, before asking the question:

“When did Noah build the ark?”

My fellow scouts and I looked at each other – confused. Did he want an exact date?!?

The scout master waited a moment for one of us to offer up some idiotic attempt at an answer – thankfully no one did – before he solemnly said:

“Before the rain”

It was one of those childhood moments that made little sense at the time, but comes back to haunt you as an adult when you are looking at what the future may hold and trying to plan for it.

# # # # # # # # # # #

Today’s post is our annual horizon scanning effort, where we lay out what is on the cards for the next 12 months with regards to clinical research focused on disease modification in Parkinson’s.

Source: Rand

We will also briefly mention other bits and pieces of preclinical work that we are keeping an eye on for any news of development.

To be clear, this post is NOT intended to be an exercise in the reading of tea leaves – no predictions will be made here. Nor is this a definitive or exhaustive guide of what the next year holds for disease modification research (if you see anything important that I have missed – please contact me). And it should certainly not be assumed that any of the treatments mentioned below are going to be silver bullets or magical elixirs that are going to “cure” the condition.

In the introduction to last year’s outlook, I wrote of the dangers of having expectations (Click here to read that post). I am not going to repeat that intro here, but that the same message applies as we look ahead to what 2020 holds.

Source: Unitystone

In fact, it probably applies even more for 2020, than it did for 2019.

2020 is going to be a busy year for Parkinson’s research, and I am genuinely concerned that posts like this are only going to raise expectations. My hope is that a better understanding of where things currently are and what is scheduled for the next 12 months will help in better managing those expectations. Please understand that there is still a long way to go for all of these experimental therapies.

All of that said, let’s begin:

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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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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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