Synucleinopathy begets channelopathy?

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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?

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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

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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

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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”

Is there something in the air?

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Air pollution is an international problem in the post-industrial world. Poor air quality has been associated with an increasing number of medical conditions.

For a long time there has been indications that neurodegenerative conditions – such as Parkinson’s and Alzheimer’s – could also be associated with air pollution.

Recently, several research reports have been published providing compelling evidence further supporting the association and raising new questions. 

In today’s post, we will review some of that research and discuss what could be done next (SPOILER ALERT: the solution involves needing cleaner air).

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Vast. Source: Unequal

I have been extremely fortunate in my life to have travelled to a few of the major cities of the world, but none have had as much impact on me upon arrival as Mexico city.

The pilot had announced over the loud speaker that we were approaching the outskirts of the city, and I looked out of my window to catch a first glimpse of the central American metapolis. Block after block of dwellings passed beneath us, and I thought “great, we’ll be landing soon“.

Mexico City: Really vast. Source: lsecities

Three minutes later, block after block of dwellings were still passing beneath us.

It was the first really vast city that I had ever visited.

Covering approximately 1,500 square kilometers (580 sq miles) of an old volcanic crater, the city is huge. By comparison, New York city covers only 1/2 the area (approximately 780 square kilometers or 300 sq miles – Source).

Home to over 8 million people, Mexico city was an amazing place to explore.

Palacio de Bellas Artes. Source: Turkishairlines

The art, the culture, the history, and the food – lots to see and experience!

Bosque de Chapultepec. Source: Jetsetter

But like all big cities, Mexico city has its share of problems. In addtion to sinking more than 10 metres over the past century (Click here to read more about this), Mexico City also has a terrible air population problem.

And this latter issue has recently been implicated in some Parkinson’s related research.

What do you mean?

Continue reading “Is there something in the air?”

The PASADENA study announcement (part 2)

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In April of this year it was announced that the closely watched Phase II PASADENA clinical trial had not to met its primary objective. This was a large clinical evaluation of an immunotherapy approach (called prasinezumab) for disease modification in Parkinson’s. 

At the time of the announcement, it was indicated that the researchers who conducted the study had seen “signals of efficacy” in the data.

This week the results of the study were presented at an international conference and it was reported that prasinezumab “significantly reduced decline in motor function by 35% (pooled dose levels) vs. placebo after one year of treatment“.

In today’s post, we will discuss what the PASADENA study was, review the results that have been released, and discuss what might happen next.

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At 7am (just prior to the opening of the Swiss Stock Exchange) on Wednesday 22nd April 2020, the pharmaceutical company Roche published its sales results for the 1st Quarter. The financial report looked good, particularly considering the current COVID-19 economic climate, but there was one sentence on page 133 of the results (highlighted below) that grabbed a lot of attention:

From page 133. Source: Roche

For those of you (like myself) who struggle with fine print, the sentence reads:

Study did not meet its primary objective, but showed signals of efficacy

This was how the Parkinson’s community found out about the top line result of the closely followed Phase II PASADENA study evaluating the immunotherapy treatment prasinezumab in individuals recently diagnosed with Parkinson’s.

Many within the Parkinson’s community were basically:

Yet another negative clinical trial result.

But then, later that same day, the biotech firm Prothena – which developed prasinezumab and is partnered with Roche in the clinical testing – kindly provided a press release.

And in that document, the company repeated that prasinezumab “showed signals of efficacy, but importantly: “These signals were observed on multiple prespecified secondary and exploratory clinical endpoints“.

And then the Parkinson’s community was like:

This week we found out more about those “signals of efficacy” and the results of the PASADENA study, and they look interesting.

What do the results show?

Continue reading “The PASADENA study announcement (part 2)”

The hunt for a vaccine

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This week, the biotech firm AFFiRiS published the long awaited results of their Phase 1 clinical trial evaluating a vaccine for Parkinson’s. The vaccine – called PD01A – targets a protein that clumps/aggregates together in certain neurons in the brains of people with Parkinson’s.

The multi-year study suggests that the treatment is safe and tolerated. In addition, it causes the immune system to generate antibodies that target the aggregated form of alpha synuclein.

And while it must be remembered that this is a small, open-label study, there are some intriguing statements made in the report.

In today’s post, we will discuss what PD01A is, review the results of the clinical study, and explore what happens next.

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Source: NHI

As the world awaits the development of a vaccine that will combat COVID-19, the neurodegenerative research community has quietly been watching a biotech company in Austria that has been developing a vaccine of a different sort: A vaccine for Parkinson’s.

The company is called AFFiRiS:

Source: Twitter

And this week they published the results of their Phase 1 safety/tolerability clinical trial of their immunotherapy treatment (PD01A) that they are testing in people with recently diagnosed Parkinson’s.

What is immunotherapy?

Continue reading “The hunt for a vaccine”

Disney’s “Attack of the synucleozid from Jupiter”

 

Alpha synuclein is widely viewed as one of the bad guys in Parkinson’s. The clustering and aggregation of this protein is one of the main pathological hallmarks of the condition.

Researchers led by scientists at the Scripps Research institute in Florida have developed a new drug-like compound that selectively prevents the production of alpha synuclein protein.

They have called their new compound “synucleozid“.

In today’s post, we will look at what alpha synuclein is, what synucleozid does, and how this approach could potentially help in treating Parkinson’s.

 


 

 

In a recent SoPD post, we discussed research focused on levodopa-induced dyskinesias which was led by scientists from the Scripps Research Institute (Click here to read that post). The Scripps is the largest private, not-for-profit medical research facility in the United States and among the largest in the world.

It is headquartered in La Jolla, California, but interesting fact: It has a sister facility in Jupiter, Florida.

Scripps Research in Jupiter. Source: Weitz

Officially opened on February 26th 2009, the establishment of the Scripps Florida campus was made possible by a one-time US$310 million federal economic development fund. The institute now survives on research grants, gifts, and contracts. In the future, some of the funding may also come from royalties generated by intelluctual property based on medical discoveries made at the facilities.

And some of those medical discoveries may involve novel ways to treat Parkinson’s.

Really? Such as?

Recently a research team led by Professor Matthew Disney published a report that takes an interesting approach towards trying to tackle Parkinson’s.

Professor Matthew Disney. Source: Scripps

What does it involve?

It involves reducing levels of the Parkinson’s associated protein alpha synuclein.

What is alpha synuclein?

Continue reading “Disney’s “Attack of the synucleozid from Jupiter””

Putting the PARKIN back into Parkinson’s

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Genetic variations in a region of our DNA called PARKIN is associated with an increased risk of developing Parkinson’s – particularly young-onset PD (diagnosed before the age of 40yrs).

This area of DNA provides the instructions for making a protein (also referred to as PARKIN), which plays a number of important roles inside of cells.

Recently, a South Korean biotech company called Cellivery has published research on an experimental therapeutic agent that easily penetrates both the brain and cells within, delivering PARKIN protein to the cells that need it.

In today’s post, we will discuss what PARKIN does, review the new research report, and explore what could happen next.

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Source: Quanta

Here on the SoPD we often talk about research regarding the prominent Parkinson’s associated proteins, think of alpha synuclein, LRRK2 and GBA. And they are of interest as there is a great deal of activity now at the clinical level exploring agents targetting these proteins.

But there are a number of interesting therapeutics being developed that are exploring some of the other Parkinson’s-associated proteins.

A good example was published this week:

Title: Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein
Authors: Chung E, Choi Y, Park J, Nah W, Park J, Jung Y, Lee J, Lee H, Park S, Hwang S, Kim S, Lee J, Min D, Jo J, Kang S, Jung M, Lee PH, Ruley HE & Jo D
Journal: Science Advances, 29 Apr 2020:6, 18, eaba1193
PMID: N/A

In this study, South Korean researchers demonstrated that a brain penetrating compound (including the PARKIN protein) can rescue numerous models of Parkinson’s.

Hang on a second: What is PARKIN?

Continue reading “Putting the PARKIN back into Parkinson’s”

The Pasadena study announcement

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This week the outcome of an ongoing Parkinson’s clinical trial was announced.

Data collected during Part 1 of the ongoing Phase 2 PASADENA alpha synuclein immunotherapy study for Parkinson’s apparently suggests that the treatment – called prasinezumab – has not achieved it’s primary endpoint (the pre-determined measure of whether the agent has an effect in slowing Parkinson’s progression – in this case the UPDRS clinical rating scale).

But, intriguingly, the announcement did suggest ‘signals of efficacy‘ in secondary and exploratory measures.

In today’s post, we will discuss what immunotherapy is, what we know about the PASADENA study, and why no one should be over reacting to this announcement.

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At 7am on Wednesday, April 22nd, 2020, the pharmaceutical company Roche published its sales results for the 1st Quarter. This was just prior to the opening of the Swiss Stock Exchange. The financial report looked very good, particularly considering the current COVID-19 economic climate.

There was, however, one sentence on page 133 of the results that grabbed some attention:

Source: Roche

For those of you (like myself) who struggle with fine print, the sentence reads:

Study did not meet its primary objective, but showed signals of efficacy

This was how the pharmaceutical giant announced the top line result of the ongoing Phase II PASADENA study evaluating the immunotherapy treatment prasinezumab in recently diagnosed individuals with Parkinson’s (listed on the Clinicaltrials.gov as NCT03100149).

At the time of publishing this SoPD post, Roche are yet to provide any further information (press release, announcement, memo, tweet, etc) regarding the results of the study.

Thankfully, a smaller biotech firm called Prothena – which is also involved in the development of the agent being tested in the Pasadena study – has kindly provided a few more details regarding these results.

I usually don’t like discussing clinical trial results on the SoPD until the final report is published, but in this circumstance I will make an exception.

In today’s post we will discuss what details have been shared in the Prothena press release regarding the Prasinezumab clinical trial in Parkinson’s (Click here to read the press release).

What is Prasinezumab?

Continue reading “The Pasadena study announcement”