Tag: alpha synuclein

The seeds of change

~ Simon ~ 1 Comment

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The diagnostic process for Parkinson’s has been problematic for a long time. Individuals presenting the symptoms often need several clinical evaluations, and confirmation using a brain imaging technique.

A biological test for the condition has been lacking and would help tremendously.

Recently, however, research (supported by the Michael J Fox Foundation for Parkinson’s research) has indicated that this could be about to change.

In today’s post, we will explore recently published research highlighting a new potential biomarker test for Parkinson’s.

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On the 27th June, 1997, a research report was published in the prestigious scientific journal ‘Science’ that would change the world of Parkinson’s forever.

And I am not exaggerating or overstating here. I know I can sometimes be a little over the top, but the research report in question very much changed the world of Parkinson’s research.

The discovery that tiny variations in a region of DNA that scientists refer to as “alpha synuclein” could increase the risk of developing Parkinson’s gave researchers their first real insights into some of the biology that could potentially be underlying the condition (Click here to read a previous SoPD post on this discovery):

Science

Title: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease.
Authors: Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL.
Journal: Science. 1997 Jun 27;276(5321):2045-7.
PMID: 9197268

And then – remarkably just two months later – the results of another study were published in the journal ‘Nature’, and these would further cemented alpha synuclein’s place in Parkinson’s research.

In this second research paper, the investigators showed that alpha synuclein was present in “Lewy bodies” – densely packed spheres of protein inside of cells that are one of the characteristic features of the Parkinsonian brain:

Title: Alpha-synuclein in Lewy bodies.
Authors: Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M.
Journal: Nature. 1997 Aug 28;388(6645):839-40.
PMID: 9278044

And very suddenly, this poor little protein became public ‘enemy number one’ for the Parkinson’s research community and everyone started digging into the biology associated with it with the hope of finding new avenues for therapeutic intervention and biomarkers for Parkinson’s.

What exactly is alpha synuclein?

Continue reading “The seeds of change” →

Slow-wave sleep saves synucleinopathy?

~ Simon ~ 14 Comments

 

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Good sleep patterns have important implications for all of us in terms of health and well being, but sleep is often disrupted for people with Parkinson’s.

Research suggests that people with Parkinson’s have reduced amounts of slow wave and REM sleep, and increased periods of wakefulness.

A new report has found that increasing levels of slow wave sleep could have beneficial effects in reducing the accumulation of alpha synuclein protein in the brain.

In today’s post, we will discuss what sleep is, how it is affected in Parkinson’s, and what the new research indicates about slow wave sleep.

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Source: Dlanham

I am a night owl.

One that is extremely reluctant to give up each day to [the waste of precious time that is] sleep. There is always something else that can be done before going to bed. And I can often be found pottering around at 1 or 2am on a week night.

Heck, most of the SoPD posts are written in the wee small hours (hence all of the typos).


Source: Iristech

As a result of this foolish attitude, I am probably one of the many who live in a state of sleep deprivation – I am a little bit nervous about doing the spoon test:

And the true stupidity of my reluctance to adopt a healthy sleep pattern is that I fully understand that sleep is extremely important for our general level of health and well being.

In addition, I am also well aware of an accumulating pool of research that suggests sleep could be influential in the initiation and progression of neurodegenerative conditions, like Parkinson’s.

Wait, how is sleep associated with Parkinson’s?

Continue reading “Slow-wave sleep saves synucleinopathy?” →

ADepTing to the UCB-Novartis deal

~ Simon ~ 6 Comments

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Alpha synuclein has long been viewed at “Public enemy #1” by the Parkinson’s research community. This sticky, abundant protein starts to cluster (or aggregate) in Parkinson’s.

There have been several attempts to reduce levels of the protein floating around outside of cells (using “immunotherapy” approaches)

But now clinical research is ramping up to determine if reducing aggregated alpha synuclein levels in the brain could help to slow/stop the progression of the condition.

In today’s post, we will look at three different lines of clinical research focused on small molecule inhibitors of alpha synuclein aggregation. 

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When someone mentions the pharmaceutical firm Novartis, it feels like the company has been around forever, but it is actually not that old.

It was created in March 1996 via the merger of two Swiss companies: Ciba-Geigy and Sandoz. The roots of those companies can be traced back more than 250 years, but the combined entity is still a spring chicken compared to many of its major competitors.

The name Novartis results from the combination of two words “Nova Artes”, which means new art and innovation in simple forms, but there is little in what the company does that is ‘simple’. A good example of this was their block buster cancer drug Gleevec/Glivec (imatinib) which was developed by careful “rational drug design” for very specific types of cancer.

Source: NCBI

The reputation for Swiss precision seems to flow through this company and they are always making very carefully placed bets.

Which makes their news this week rather interesting.

What news did they have?

Continue reading “ADepTing to the UCB-Novartis deal” →

Mo better for TEVA with Modag?

~ Simon ~ 3 Comments

 

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This week the pharmaceutical company TEVA Pharmaceuticals Industries Ltd has announced a deal with a small German biotech firm called MODAG.

The two companies are forming a strategic collaboration on the exclusive worldwide licensing and development of MODAG’s lead compound anle138b.

Anle138b is a small molecule inhibitor of the believed to be toxic forms of the Parkinson’s-associated protein alpha synuclein.

In today’s post, we will discuss what is known about anle138b and the implications of this new partnership.

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Source: SLE

In 1901, Haim Salomon and his brother-in-law Moshe Levin established a small wholesale drug business, near the Nablus Gate in Jerusalem. They called it “Salomon and Levin”. A few years later, Yitzhak Elstein, another of Haim Salomon’s brothers-in-law, joined the firm and they changed the name of the company to SLE – Salomon Levin and Elstein.

Source: SLE

From these humble beginning, grew a pharmaceutical juggernaut that we know today as TEVA Pharmaceuticals.

TEVA – meaning “Nature” in Hebrew – is now an international producer of pharmaceutical agents, with 40,000 employees working across 65 manufacturing facilities in more than 30 countries. The company has a portfolio of more than 3,500 medicines, and they produce approximately 85 billion tablets and capsules per year (Source).

Does TEVA produce any drugs for Parkinson’s?

Yes, Azilect (rasagiline) – an approved monoamine-oxidase B inhibitor for the treatment of Parkinson’s – was developed by Teva Pharmaceuticals.

In addition, they are actively developing novel therapies. And this week they signed a really interesting deal to collaborate with a small German biotech company called MODAG.

What does MODAG do?

Continue reading “Mo better for TEVA with Modag?” →

Does immunotherapy need therapy?

~ Simon ~ 10 Comments

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Over the last decade, a large number of clinical trials involving immunotherapy have been conducted in the field of Alzheimer’s research. The overall success rate of these studies has not been encouraging.

Immunotherapy involves artificially boosting the immune system so that it targets of particular pathogen – like a rogue protein in the case of Alzheimer’s – and clears it from the body.

Recently, preclinical research has pointed to several possible reasons why this approach may be struggling in the clinical trials, and potential solutions that could be explored.

In today’s post, we will review two research reports and consider how this applies to Parkinson’s research.

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Immune cells (blue) checking out a suspect cell. Source: Lindau-nobel

Immunotherapy is a method of boosting the body’s immune system to better fight a particular disease. Think of it as training the immune cells in your body to target a particular protein.

The approach involves utilising the immune system of your body, and artificially altering it to target a particular protein/disease-causing agent that is not usually recognised as a pathogen (a disease causing agent).

It is truly remarkable that we have gone from painting on cave walls to flying helicopters on Mars and therapeutically manipulating our body’s primary defense system.

Immunotherapy is potentially a very powerful method for treating a wide range of medical conditions. To date, the majority of the research on immunotherapies have focused on the field of oncology (‘cancer’). Numerous methods of immunotherapy have been developed for cancer and are currently being tested in the clinic (Click here to read more about immunotherapy for cancer).

Many approaches to immunotherapy against cancer. Source: Bloomberg

Immunotherapy has also been tested in neurodegenerative conditions, like Alzheimer’s and more recently Parkinson’s. It typically involves researchers carefully designing antibodies that target a rogue protein (like beta amyloid in Alzheimer’s and alpha synuclein in Parkinson’s) which begin to cluster together, and this aggregation of protein is believed to lead to neurotoxicity.

Source: RND

What are antibodies?

Continue reading “Does immunotherapy need therapy?” →

UCB at ANN looks A-OK

~ Simon ~ 3 Comments

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Alpha synuclein is one of the most common proteins in our brains and it has long been associated with Parkinson’s. The protein appears to clump together forming dense clusters ( or “aggregates“) in the Parkinsonian brain, and this may be related to the progressive neurodegeneration.

Researchers have been desperately seeking small molecules that will break up (or dissociate) these aggregates in the hope that it will slow down the progression of PD and allow neurons to return to health.

One example of such a molecule is UCB0599, which is being clinically developed by the pharmaceutical company UCB. This week, UCB presented the first clinical results for UCB0599 from their Phase I trial.

In today’s post, we will look at what alpha synuclein is, review what is known about UCB0599, discuss the results of the study, and consider what comes next.

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Source: AAN

Last week at the 2021 American Academy of Neurology virtual meeting a poster was presented by the pharmaceutical company UCB.

Here at SoPD HQ, we have been eagerly awaiting these results.

They were the findings from the first Phase I clinical trial of a new molecule called UCB0599.

What is UCB0599?

UCB0599 is a brain-penetrant, oral small molecule alpha-synuclein misfolding inhibitor.

What does that mean?

Continue reading “UCB at ANN looks A-OK” →

Synucleinopathy begets channelopathy?

~ Simon ~ 1 Comment

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Alpha synuclein is a protein that is closely associated with Parkinson’s. It was the first gene to be associated with increased risk of developing Parkinson’s, and the alpha synuclein protein was found to be present in Lewy bodies – a characteristic feature of the Parkinson’s brain.

As a result of this association, researcher have used high levels of this protein to model Parkinson’s in cell culture and animal experiments. 

Recently, scientists have reported that high levels of alpha synuclein can cause shrinkage of motorneurons, resulting in a reduction of gut motility in mice – potentially connecting multiple features of Parkinson’s in one study.

In today’s post, we will review the results of this new study and consider what could happen next.

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Channelopathy conditions. Source: Frontiers

A reader recently emailed me to ask if Parkinson’s is a channelopathy?

It’s a good question.

What is a channelopathy?

Channelopathies are conditions caused by disruption of the function of proteins involved in ion channels or the proteins that regulate them. These diseases can be either congenital (present from birth, often resulting from a genetic mutation) or acquired (often resulting from an insult such as autoimmune attack or toxin on a particular type of ion channel – click here to read a good review on this topic).

Hang on a second, what are ion channels?

Ion channels are protein structures in membranes that allow certain elements to pass through them into (or out of) the interior of a cell.

Source: Biologydictionary

These conduits play critical roles in many processes of normal cellular life – from passing signals between cells to general cellular well being (homeostasis). Many of these channels are very selective in what they allow to pass (for example, there are calcium channels and sodium channels which only allow calcium and sodium to pass, respectively).

When components of a channel are disrupted (resulting in dysfunctional activity in that channel), it can have serious implications for cells and the organisms that they inhabit.

Can you give an example of a disease that is a channelopathy?

Spinocerebellar ataxia type 6 (or SCA6) can be used as an example of a channelopathy.

Spinocerebellar ataxia are a collection of rare, genetic condition that is characterized by slowly progressive cerebellar ataxia (a lack of muscle coordination that can make speech and movement difficult) and nystagmus (involuntary, uncontrollable eye movements).

This video explains what spinocerebellar ataxia are:

SCA6 is a late onset form of spinocerebellar ataxia (typically starting after 65 years of age) – many people with SCA6 can be misdiagnosed with ALS or Parkinson’s. SCA6 is caused by mutations in CACNA1A, a gene that provides the instructions for making one part (the alpha-1 subunit) of a calcium channel called CaV2.1.

Very interesting. But how does this relate to Parkinson’s?

Continue reading “Synucleinopathy begets channelopathy?” →

What is GDNF without RET?

~ Simon ~ 2 Comments

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Neurotrophic factors – like Glial cell line-derived neurotrophic factor (or GDNF) – hold great hope for regenerative therapy in Parkinson’s research. New research, however, indicates that simply injecting the protein into the brain may not be enough.

Scientists at Rush University Medical Center (in Chicago) conducted a postmortem analysis of brains from people who passed away with Parkinson’s and made an intriguing discovery.

They found that many of the remaining dopamine neurons appear to not be producing a protein called Ret, which is required for GDNF signaling. In addition, other components of GDNF signaling pathway were missing. 

In today’s post, we will review the background of this new study, outline what the study found, and discuss the implications of the research.

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GDNF. Source: Wikipedia

Glial cell line-derived neurotrophic factor (or GDNF) is a topic that gets a lot of reader attention on the SoPD. It is a tiny protein that holds great hope for the Parkinson’s community in terms of providing a potential neuroprotective and regenerative therapy.

GDNF is a type of neurotrophic factor, which are small naturally-occurring proteins that nurture neurons and support their growth. There are different kinds of neurotrophic factors, and the testing of some of them in preclinical models of Parkinson’s has generated encouraging results (particularly in the case of GDNF – click here to read a previous SoPD post on this topic).

But the translation of those initial results in cell culture and animal models of Parkinson’s has been difficult in clinical trials of neurotrophic factors.

This has led to many questions being asked within the research community about the nature of biological signaling pathways involved with neurotrophic factors and whether they might be affected in Parkinson’s.

The majority of the neurotrophic factors that have been tested in models of Parkinson’s and in clinical trials for Parkinson’s belong to a branch that requires the RET signaling pathway to be available to have their neuroprotective effect.

What is the RET signaling pathway?

Continue reading “What is GDNF without RET?” →

Being ly-mphatic about drainage issues

~ Simon ~ 11 Comments

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The lymphatic network is an important part of our body’s defense system. It is made up of an enormous web of vessels and nodes which help to protect us from infection and disease.

This network transports a colourless fluid (called lymph), which serves two primary functions: 1.) it contains infection-fighting white blood cells that help in immune responses, and 2.) it functions as a ‘drainage system’ – allowing excess fluid from organs to be extracted and shifted to the blood system for excretion.

Recently, researchers reported something interesting about the lymphatic system in people with Parkinson’s: the rate of flow around the brain is slower.

In today’s post, we will discuss what the lymphatic system is, review what the new research found, and look at how this new information could potentially be used to help treat conditions like Parkinson’s.

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Source: Thinkery

So picture this if you will:

The weather reporter would later say that it was “a month of rain in the matter of an hour“, but in the midst of the summertime mêlée I was standing bare foot, ankle deep in my rapidly flooding courtyard, trying to clear the blocked storm drain with a long metal pole.

My tee-shirt and shorts were soaked, and… oh yeah, there was lots of thunder and (more importantly) lightning.

Source: KalingaTV

Now, I am a rather tall individual (6’8 ~ 2m 7cm on my good days), and looking back now I can appreciate that standing ankle deep in water holding a long metal pole high in the air (to gather enough downward force to unplug the drain) in the middle of a lightning storm was probably not one of my best moments.

Luckily, my neighbour – a plumber and 3-4 fold smarter than me – kindly decided to take pity on his slow-witted nearby resident. He leapt into the situation and resolved it all in the blink of an eye.

Source: Independent

Since that moment I have religiously maintained a clear storm drain, and taken to deriving great pleasure in keeping other drainage systems about the house clear and flowing free.

I’m happy for you, but what does this have to do with Parkinson’s?

Well, very recently researchers have reported that a different kind of drainage issue might be at play in many cases of Parkinson’s.

What on Earth do you mean?!?

Continue reading “Being ly-mphatic about drainage issues” →

T-cells: First responders

~ Simon ~ 5 Comments

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The cause of the cell loss and pathology associated with Parkinson’s is still unknown. While the later stages of the condition have been well investigated based on various pathological marker (ie Braak staging), the early manifestations of the condition are still a mystery.

Cells of the immune system are early responders to any signs of trouble in our bodies, and recently researchers have been looking at a specific class of immune cells (called T cells) in postmortem sections of brains from people who passed away with Parkinson’s.

Curiously, in their analysis the researchers found that the bulk of activity of T cells occurs before any cell loss or pathology appears.

In today’s post, we will discuss what T cells are, review the new research, and explore what this could mean for potential therapies for Parkinson’s.

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Your hematopoietic system. Source: Wikipedia

The process of hematopoiesis (or blood formation) is absolutely fascinating.

Seriously.

You start off with a single, multi-potential hematopoietic stem cell. This is called a hemocytoblast (it’s the big cell in middle of the image below):

A hemocytoblast. Source: Pinterest

Given enough time, this single cell will give rise to an entire blood system, made up of many of different types of cells with very specific functions that are required for us to live normal lives.

It is a remarkable achievement of biology.

Understand that at any moment in time your blood system will contain 20-30 trillion cells (in the average human body). And as the image near the top of the post suggests, there are quite a few branches of potential cell types that these blood stem cells can generate.

Very interesting, but what does this have to do with Parkinson’s?

Continue reading “T-cells: First responders” →