Synucleinopathy begets channelopathy?

# # # #

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.

# # # #


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?

# # # #

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.

# # # #

 

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?”

Bringing Joy to Parkinson’s research

# # # #

Today’s post was a joy to write.

It is one of those stories that will ultimately become the stuff of legend. And other areas of medical research will come to envy the fact that they don’t have a similar compelling tale. It is such a fascinating story that one feels fortunate to be a researcher living through the period of time during which it is actually unfolding.

The background of the narrative is really simple: A lady in an audience made a wonderous association, and then had the courage to publicly ask an odd question (“Why do people with Parkinson’s smell different?“). An intrepid researcher then had the curiosity to follow up on that question, and the resulting findings have opened up amazing new opportunities for us.

Recently researchers in Manchester (and their collaborators) have published a series of updates on their research exploring the “smell of Parkinson’s” 

In today’s post, we will discuss what they have found and how their research could potentially affect our understanding of and approach to Parkinson’s.

# # # #


Dr Les Milne. Source: BBC

Dr Les Milne was a consultant anaesthesiologist at Macclesfield in Cheshire for 25 years.

He was one of the first medical directors in the Mersey region, at one point having five departments under his management. Instrumental in changing the training of theatre operating assistants in the hospital, Les was known for giving up his own time to provide extra training to trainees to help them get their qualifications. His was an impressive career.

It is said that beside every great man, there is a great woman, and Les met his when he was 17.

Her name was Joy:

Joy Milne. Source: Telegraph

When Les was 31 year old, he came home one evening, and Joy noticed something different about him.

Specifically, he smelled different.

His lovely male musk smell had got this overpowering sort of nasty yeast smell,” she says (Source).

It was a “sort of woody, musky odour” Joy suggests, and she “started suggesting tactfully to him that he wasn’t showering enough or cleaning his teeth. He clearly didn’t smell it and was quite adamant that he was washing properly.” (Source).

Joy, who had trained as a nurse, let the matter go, but as we shall see this simple observation was to have important ramifications.

What happened?

Continue reading “Bringing Joy to Parkinson’s research”

Isradipine: Posthoc analysis

# # # #

Last year the results of the large STEADY-PD study were published. The investigators behind the Phase III clinical trial reported that the experimental treatment being tested had no effect on the progression of Parkinson’s in recently diagnosed individuals.

The treatment being evaluated was a calcium channel blocker called isradipine – it is used for treating high blood pressure.

Since publishing the results, some of the researchers behind the study have been conducting post hoc analysis of the data… and they have found something interesting: An effect.

In today’s post, we will look at why isradipine was evaluated in Parkinson’s, what the results of the STEADY-PD study were, and what the newly discovered effect could mean.

# # # #


Source: Medium

In the scientific world, post hoc analysis (from the Latin post hoc, meaning “after this”) consists of statistical analyses that are specified after the data has been seen. This type of analysis should only be considered for “hypothesis forming” exercises, and not be viewed as cherry-picking of the data in order to find an effect. 

And one must be careful with interpretation of data (eg. most people who are involved in car crashes have been reported as wearing clothes at the time of the incident, thus we should get rid of clothes to assess if this will reduce the incidence of automobile accidents).

Post hoc analyses of completed clinical trial data, however, can be very useful process of identifying interesting trends that could be explored in future studies.

A good example of this has recently been conducted on the STEADY-PD clinical trial study.

What was the STEADY-PD clinical trial about?

Continue reading “Isradipine: Posthoc analysis”

What TDO about KMO?

# # # #

New approaches for potentially slowing the progression of Parkinson’s are being announced on a regular basis. Some of them can not be independently replicated (such is the nature of science), while others open up whole new areas of research.

Recently scientists have reported that inhibiting certain aspects of the kynurenine pathway – which plays a critical role in generating energy in cells – can have neuroprotective results in models of Parkinson’s.

Many of the results have been independently replicated and the findings are now resulting in a new class of drug heading for clinical testing.

In today’s post, we will delve into what the kynurenine pathway is, explore how it relates to Parkinson’s, and discuss some of the approaches soon heading for the clinic.

# # # #


Structure of tryptophan. Source: Wikipedia

Tryptophan is one of eight essential amino acids.

Amino acids are the fundamental building blocks of proteins in biology, but the “essential” label in this case does not refer to its necessity (although it is necessary), but rather the fact that it cannot be made by our bodies. As a result, all essential amino acids must come from the food we consume.

Tryptophan has many functions within the body:

  • it is a precursor to the neurotransmitter serotonin (which influences your mood, cognition, and behaviour)
  • it is a precursor of the hormone melatonin (which governs your sleep-wake cycle)
  • it is a precursor of vitamin B3 (naicin)

Source: Wikimedia

More importantly, however, tryptophan is also involved in kynurenine synthesis.

What is kynurenine synthesis?

Continue reading “What TDO about KMO?”

Monthly Research Review – February 2021

# # # #

At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during February 2021.

The post is divided into eight parts based on the type of research:

# # # #


So, what happened during February 2021?

In world news:

February 4th – More injections than infections – more people have now been vaccinated against Covid-19 than infected worldwide (Source).

February 15th – Ngozi Okonjo-Iweala elected as the seventh Director-General of the World Trade Organisation – a first for women and a first for Africa (Source).

 

February 17th – Researchers reported a high-performance polyethylene plastic made from renewable oils that is chemically recyclable (Source).

February 18th – Nasa’s Perseverance (“Percy”) rover was safely delivered to the surface of Mars (Source).

24 February – Ghana becomes the first country to receive vaccines through the COVAX vaccine-sharing initiative.

 

In the world of Parkinson’s research, a great deal of new research and news was reported:

In February 2021, there were 1,228 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (2,463 for all of 2021 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 5 pieces of Parkinson’s news

Continue reading “Monthly Research Review – February 2021”

Forget Special K, maybe focus on LysoK

# # # #

Over the last 20 years, researchers have identified a number of genetic variations that can confer an increased risk of developing Parkinson’s. Tiny alterations in regions of DNA (called genes) – which provide the instructions for making a protein – can increase one’s chances of Parkinson’s.

A better understanding of the biological pathways associated with these genetic risk factors is opening up vast new areas of research.

Recently researchers have been exploring the biology behind one particular genetic risk factor – involving a gene called TMEM175 – and they have discovered something quite unexpected: While one genetic variation in the TMEM175 gene increases the risk of Parkinson’s, another variation reduces it.

In today’s post, we will explore the biology of TMEM175, review what the results of the new research indicate, and consider why these findings might be interesting in terms of potential future therapeutic targets.

# # # #


Wadlow (back left). Source: Telegraph

Robert Pershing Wadlow was always in the back of school photos.

Born February 22nd 1918, Wadlow’s birth certificate indicated that he was “normal height and weight“, but from that point onwards, there was nothing normal about his rate of growth.

By the time, Robert was 8 years old, he was taller than his father (he was 6 foot/183cm). And eight years later when he turned 16, Robert was 8 foot 1 (2.47 m)… and he was still growing.

Here is a picture of him with his family at 19 years of age:

Source: Businessinsider

Robert was the tallest person in recorded history, and at the time of his death – at the tragically young age of 22 – Robert was almost 9 feet tall (8 ft 11; 2.72 m)… and still growing.

His incredible growth was caused by a condition called hyperplasia of his pituitary gland. This condition that results in an overactive pituitary gland which causes an abnormally high level of the human growth hormone to be produced.

Source: Britannica

Human growth hormone (or somatotropin) is a peptide hormone that belongs to a much larger group of molecules that are referred to as growth factors.

In general terms, growth factors are small molecule that plays an important and fundamental role in biology. They stimulate cell proliferation, wound healing, and occasionally cellular differentiation.

And Robert’s story is an example of how powerful the effect these tiny molecules can have.

Growth factors are secreted from one cell and they float around in the extracellular world until they interact with another cell and initiate survival- and growth-related processes.

Source: Wikimedia

We have often discussed growth factors on this website in the past, with posts of growth factors like GDNF (Click here to read a SoPD about this) and CDNF (Click here to read a SoPD post on this). These discussions have largely focused on how growth factors could have neuroprotective and regenerative potential for Parkinson’s, stimulating survival and growth of cells.

Recently, however, new research has been published that demonstrates how some of these growth factors could be influencing an entirely different aspect of cellular biology that is connected to Parkinson’s: lysosomal function.

What is lysosomal function?

Continue reading “Forget Special K, maybe focus on LysoK”

Our approach to failure

# # # #

Recently the results of two large clinical trials in Parkinson’s were announced. Both indicated that the therapies involved had not demonstrated any impact on the progression of Parkinson’s. This disappointing news resulted in the usual headlines (“Epic failure” & “Clinical trial tanks”) from news outlets whose editors have obviously never lost anyone they cared about.

In addition, there has also been a useful chorus of “I told you so” and “We’re going the wrong way” coming from the back seat of the car, despite the fact that we haven’t seen any actual trial data yet, or the fact that they can’t propose any viable alternative approaches.

What is missing in all of this noise, however, is a better approach to failure. Not only an open and honest postmortem of what worked and didn’t work in the studies, but also better, more respectful ways of communicating results.

In today’s post, we will discuss our approach to failure.

# # # #


PART 1. POSTMORTEM

The book I gift the most is Sherwin Nuland’s “How we die”.

As a rule, I am selective as to who I gift this to, never for Christmas or birthdays, and I always remind the receiver of the gift that “you should not judge a book by its cover”.

This book is so precious.

A poetic set of reflections from a medical doctor who has sent his entire career watching ‘life’s final chapter’. There is science, wisdom and beauty on every single page. Nuland has such a wonderful way with words, and I find myself constantly going back to this book and finding something new.

Sherwin Nuland (1930 – 2014). Source: Theparisreview

My favourite part of the entire book is chapter 11.

Throughout the first half of the book, Nuland pushes the argument for returning some dignity to our last days of life. Rather than prolonging suffering in a futile effort to extend life a few short months, he implores the reader to let nature simply take its course.

But all of this changes in chapter 11, where he describes the moment his brother Harvey called him on the phone and told him he had been diagnosed with terminal cancer.

Source: Lawtech

In an instant everything changed. The context had shifted, and instead of “let nature simply take its course”, Nuland recalls how his thinking immediately became “we have to do whatever it takes to keep my brother alive”. (And I’m not ruining the book by sharing this spoiler – there is so much more in this book. It should be required reading for first year medical students).

My second most gifted book is “Black box thinking: The Surprising Truth About Success by Matthew Syed.

Matthew Syed. Source: Amazon

It investigates how we approach failure, and the first chapter describes everything that is wrong with how we currently conduct clinical trials.

What does it say?

Continue reading “Our approach to failure”

The basket case

# # # #

One of the more interesting pieces of clinical trial news in 2020 was the publication of the results of a “basket study” for neurological conditions. This was a trial that involved a drug being tested on a selection of neurodegenerative conditions, rather than just one condition.

Between December 2013 to May 2017, researchers recruited a total of 29 individuals with Alzheimer’s, 14 with progressive supranuclear palsy (PSP) and 30 with corticobasal syndrome. These participants were intravenously injected with the same drug (TPI-287 – a microtubule stabilizer) once every 3 weeks for 9 weeks (with an optional 6-week open-label extension).

Although the findings of the study did not support further development of TPI-287 for tauopathies, the overall structure of the study represents an interesting example of how researchers are taking different approaches to investigating neurodegenerative conditions.

In today’s post, we will discuss novel clinical trial designs (“baskets and umbrella”) and other examples of research efforts to better understand neurodegeneration as a whole.

# # # #


Source: HuffPost

It was when my daughter turned 3 years old that the psychological warfare really started.

And I remember the moment of realisation very clearly: It began with her desire for a pet dog.

Up until that point in time, she had limited experience with dogs and her negotiation strategies centred solely around crying. I think she loved “the idea” of a dog, but she was generally quite timid around them. Regardless, she gradually began applying pressure (read: lots of crying) on us to get a dog.

And said pressure began to build rapidly (read: frequent episodes of lots of crying).

Source: Focus

Now my wife is definitely not a dog person (“wet, filthy, smelly things“). I on the other hand quite like dogs, but I was utterly, utterly, utterly opposed to getting one because I know full well who will be lumped with the mid-winter late night “walkies” two years down the line: me!

The pressure from our daughter continued to increase, however, until we finally had to sit down with her and explain that we were not going to be getting a dog. On the surface, it looked like she handled this news very well (that is to say: she did not cry). She simply accepted the situation, got up and left the room, saying “Ok”.

My wife and I looked at each other and thought “problem solved”.

The next morning, however, this picture was waiting for us on the kitchen table:

I kid you not.

That’s my daughter and her pet dog (“Linguine“) on the right, and I’m the big, cross-eyed, bad guy on the left.

Since that time the psychological manoeuvring has only become more sophisticated (the teenage years are still a few years away, but I am already absolutely terrified!).

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

Continue reading “The basket case”

Trying to LIMP-2 the lysosome

# # # #

Lysosomes are small bags of enzymes that are used to break down material inside of cells – digesting newly absorbed food or recycling old/used proteins and rubbish. Recently researchers have been discovering increasing evidence that points towards dysfunction in lysosomes as a key influential player in neurodegenerative conditions, like Parkinson’s.

There are several Parkinson’s genetic risk factors associated with lysosomal function (GBA being the obvious one), that can increase one’s risk of developing Parkinson’s.

But there is also data indicating that individuals without any of these risk factors may also have reduced lysosomal activity. And recently researchers have identified one possible explanation.

In today’s post, we will explore what lysosomes are, investigate how they maybe involved with Parkinson’s, review what the new data reports, and discuss how this information might be useful.

# # # #


Type of endocytosis. Source: Slidemodel

On a continual basis, cells inside your body are absorbing material from the world around them with the aim of collecting all that they need to survive. They do this predominantly via a process called endocytosis, in which a small part of the cell membrane envelopes around an object (or objects) and it is brought inside the cell.

As the section of cell membrane enters the interior of the cell, it detaches from the membranes and forms what is called an endosomes (sometimes it is also called a vacuole). Once inside, the endosome transported deeper into the interior of the cells where it will bind to another small bag that is full of digestive enzymes that help to break down the contents of the endosome.

This second bag is called a lysosome.

Lysosomes

How lysosomes work. Source: Prezi

Once bound, the lysosome and the endosome/vacuole will fuse together and the enzymes from the lysosome will be unleashed on the material contained in the vacuole. The digestion that follows will break down the material into more manageable components that the cell needs to function and survive.

This enzymatic process works in a very similar fashion to the commercial products that you use for washing your clothes.

Enzymatic degradation. Source: Samvirke

The reagents that you put into the washing machine with your clothes contain a multitude of enzymes, each of which help to break down the dirty, bacteria, flakes of skin, etc that cling to your clothes. Each enzyme breaks down a particular protein, fat or such like. And this situation is very similar to the collection of enzymes in the lysosome. Each enzyme has a particular task and all of them are needed to break down the contents of the endosome.

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

Continue reading “Trying to LIMP-2 the lysosome”