York: #Parkinsons2018

 

On the 12th and 13th November, Parkinson’s UK held their biennial research conference in York.

It is not only an opportunity for the charity to showcase some of the research that they have funded over the last few years, but it was also a chance for members of the Parkinson’s research community to come together to share ideas, network and form new collaborations.

I was lucky enough to attend the event this year, and wanted to share some of the take away messages from the conference with the readers.

In today’s post, we will review Parkinson’s UK 2018 research conference (#Parkinsons2018).

 

Parkinson’s UK is the largest Parkinson’s research and support charity in the United Kingdom. Since 2015, they have invested over £18 million in a variety of research projects focused on all aspects of Parkinson’s – from new experimental treatments to the Parkinson’s UK Brain Bank.

 

 

Every two years, Parkinson’s UK holds a conference highlighting some of the research that the organisation has funded over the last few years. The meeting is usually held in the beautiful walled city of York – lots of history and narrow streets to explore.

Th “The Shambles” in York. Source: hauntedrooms

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Mission: Not Impossible

 

 

The SoPD has a policy of not advertising or endorsing products/services.

This rule is in place to avoid any ethical/conflict of interest situations. It does little, however, to stop folks from bombarding the comments sections with links for wondrous magical cures which probably involve more ‘magical’ than actual cure.

Having said all that, every now and then I find or read about something that I think may be of interest to readers. In many of those cases, I can not vouch for the information being provided, but where I think there is the potential to stimulate the imagination of the reader, I am happy to take a chance and share it.

Today’s post is all about one such case: Not impossible labs.

 

Source: mfah

The first character in this story is a graffiti artist.

His name is Tony ‘Tempt’ Quan.

Tempt grew up in east Los Angeles, painting his name and art across the city from the 1980s onwards. He became the stuff of myth and legend – one of the most influential figures in the graffiti scene in California for a generation.

Source: Reelhouse

But that all changed in 2003, when – at 34 years of age – Tempt was diagnosed with Amyotrophic Lateral Sclerosis (or ALS).

Also known as motor neurone disease or Lou Gehrig’s disease, ALS is a neurodegenerative condition that leaves the sufferer completely paralysed. There are only two FDA-approved drugs for the treatment of ALS, but they have little if any impact on disease course.

For 6 years, Tempt lay paralysed and did not produce a single piece of art.

And that was when the second character in this story appeared.

His name was Mick Ebeling.

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Sensing seriousness about senolytics

 

Researchers are building as ever increasing amount of evidence supporting the idea that as our bodies age, there is an accumulation of cells that cease to function normally. But rather than simply dying, these ‘non-functional’ cells shut down and enter a state which is refered to as ‘senescence‘.

And scientists have also discovered that these senescent cells are not completely dormant. They are still active, but their activity can be of a rather negative flavour. And new research from the Rockefeller University suggests that these senescent cells could potentially explain certain aspects of Parkinson’s.

The good new is that a novel class of therapies are being developed to deal with senescent cells. These new drugs are called senolytics.

In today’s post, we will discuss what is meant by senescence, we will review the new data associated with Parkinson’s, and we will consider some of the interesting senolytic approaches that could be useful for PD.

 

This is not my living room… honest. Source: Youtube

Humans being are great collectors.

We may not all be hoarders – as in the image above – but everyone has extra baggage. Everybody has stuff they don’t need. And the ridiculous part of this equation is that some of that stuff is kept on despite the fact that it doesn’t even work properly any more.

The obvious question is:

Why do we hold on to stuff long after we don’t use it anymore?

Oh, and don’t get me wrong – I’m not talking about all that junk you have lying around in your house/shed.

No, I’m referring to all the senescent cells in your body.

Huh? What are senescent cells?

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We’re re-branding: It’s now called PARPinson’s

 

A new research report has been published this week which may point not only towards a new understanding of the biology of Parkinson’s, but also to potentially novel therapies which are clinically available.

These exciting new findings involve a DNA repair mechanism called ‘poly ADP ribose polymerase’ (or simply PARP) and a process of cell death called Parthanatos.

Biotech companies have developed PARP inhibitors which have been reported to rescue models of Parkinson’s. With a bit of tweaking, this class of drugs could potentially be re-purposed for Parkinson’s.

In today’s post, we will look at what PARP is, explain how PARP inhibitors work, review what previous PD research has been conducted on this topic, evaluate the new report, and consider what it means for the Parkinson’s community (Spoiler alert: this will be a long post!).

 


Source: Quotefancy

Ah, the good old days!

Remember them. Way back before Netflix. When life was sooo much easier.

You know what I’m talking about.

Back when biology was simple. Remember when DNA gave rise to RNA and RNA gave rise to protein, and that was it. Simpler times they were. Now, everything is so much more complicated. We have all manner of ‘regulatory RNA’, epigentics, splice variants, and let’s not get started on the labyrinthian world of protein folding.

Oh, how I long for the good old days.

Back when a cell could only die one of two ways: apoptosis (a carefully controlled programmed manner of death) and necrosis (cell death by injury):

Source: Researchgate

Now life is too complicated and complex beyond reason or imagination.

Let’s just take the example of cell death that I mentioned above: over the past decade, the Nomenclature Committee on Cell Death (or NCCD – I kid you not there is actually a committee for this) has written up guidelines for the definition/interpretation of ‘cell death’. And as part of that effort they have decided that there are now at least 12 (yes, 12) different ways a cell can die:

Source: Nature

For those of who are interested in reading more about all of these different kinds of cell death, click here to read NCCD committee’s most recent recommendations which were updated this year (2018). Some riveting betime reading.

Which form of cell death applies to Parkinson’s?

Now that’s a really good question!

One that has been studied and the source of debate for a very long time.

To be fair, we don’t really know. But fascinating new research published this week suggests that the Parthanatos pathway could be involved in the cell death associated with Parkinson’s.

What is Parthanatos?

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The potential benefits of missing an appendix

 

Researchers at the Van Andel Insititute in Grand Rapids, Michigan have published a research report that has garnered a lot of media attention.

You may have heard about it. It involves Parkinson’s and the appendix.

They found – using two independent databases – that the removal of the appendix dramatically reduces one’s risk of developing Parkinson’s. In addition, they also found that the healthy (non-Parkinson’s) human appendix has an abundant supply of the misfolded version of the Parkinson’s-associated protein alpha synuclein.

In today’s post, we will look at what the appendix is, what this new research report suggests, and explain why you should not rush out to get your appendix removed just yet.

 

Appendix. Source: journalofethics

I recieved a curious email last night.

It read:

Dear Simon,
Should I have my appendix chopped out?
Kind regards,
[Name removed]

Direct and to the point. The way I like things.

Today’s post is my response to that email.

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Monthly Research Review – October 2018

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 October 2018.

The post is divided into five parts based on the type of research (Basic biology, disease mechanism, clinical research, other news, and Review articles/videos). 

So, what happened during October 2018?

In world news:

1st October – The Nobel Prize in Physiology or Medicine is awarded to James P. Allison and Tasuku Honjo for their discoveries in cancer therapy (Click here for the press release).

3rd October – The Nobel Prize in Chemistry is awarded to George P. Smith, Frances Arnold, and Greg Winter for taking control of evolution and designing molecules used it for purposes that bring the greatest benefit to humankind (Click here to read the press release).

8th October – The 27th Human Tower Competition finished in Tarragona, Spain. ‘Castells’ were declared by Unesco one of the Masterpieces of the Oral and Intangible Heritage of Humanity in 2010. Look at the passion of these crazy Catalonians (seriously, take a moment and watch this video):

 

 

 

 

 

(Click here for another example – and turn the sound up to listen to the excitement in the commentator’s voice)

18th October – The auction house Christie’s announced that ‘Portrait of Edmond Belamy’ a painting generated entirely by artificial intelligence, will be sold at auction

(Yeah, I don’t understand art either)

30th October – NASA’s Parker Solar Probe spacecraft flew closer to the Sun than any other human made object, passing within 42.7 million km (26.6 million miles) from the Sun’s surface.

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

In October 2018, there were 647 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (6530 for all of 2018 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 6 pieces of Parkinson’s news

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Gene therapy: VY-AADC01 vs AXO-Lenti-PD

 

Future generations may treat conditions like Parkinson’s with DNA rather than drugs. By manipulating the DNA within a given cell, researchers can cause that cell to generate proteins that they usually do not produce.

This technique is called gene therapy, and it is currently being clinically tested in people with Parkinson’s.

Recently, one biotech firm (Voyager Therapeutics) has provided new data on an ongoing clinical trial and another company (Axovant Sciences) has announced the initiation of a clinical study.

In today’s post, we will discuss what gene therapy is, evaluate what the first company has achieved, and compare it with the clinical trial that is just starting.

 

Source: 2018.myana

At the annual American Neurology Association (ANA) meeting this year, we got an update on an ongoing clinical trial for Parkinson’s being conducted by a company called Voyager Therapeutics.

The biotech firm presented data at the meeting regarding their gene therapy approach for Parkinson’s.

What is gene therapy?

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Targeting PDE1 for PD

 

Many novel therapies are currently being clinically tested in Parkinson’s, and this week we heard the results of one clinical trial which provided some very interesting news.

Intra-Cellular Therapies has been testing their drug, ITI-214 – which is a potent and selective phosphodiesterase 1 (PDE1) inhibitor. Inhibitors of PDE1 prevent the breakdown of protein called cyclic nucleotides (cAMP, cGMP).

The results of the Intra-Cellular Therapies clinical trial suggest that in people with Parkinson’s, the drug not only improves symptoms, but also reduces dyskinesias.

In today’s post we will discuss what PDE1 is, how PDE1 inhibitors work, and what the results of the clinical trial suggest.

 

Source: 2018.myana

Every year in October, the American Neurology Association (ANA) gather in one of the major US cities to share research regarding neurological condtions, like Parkinson’s. And while I did not attend the ANA meeting this year, I was keen to hear the results of one particular clinical study.

It was a trial conducted by a company called Intra-Cellular Therapies.

And they were presenting the results of a Phase I/II trial of their experimental drug ITI-214.

What is special about ITI-214?

ITI-214 is a Phosphodiesterase inhibitor.

What is a phosphodiesterase inhibitor?

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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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When you stop going native

 

Alpha synuclein is a protein that is closely associated with Parkinson’s. But exactly if and how it is connected to the neurodegenerative process underlying the condition, remains unclear. 

Last week researchers reported that removing a particular form of alpha synuclein in mice results in a very early onset appearance of characteristics that closely resemble the features of Parkinson’s that we observe in humans. This finding has caused some excitement in the research community, as not only does this tell us more about the alpha synuclein protein, but it may also provide us with a useful, more disease-relevant mouse model for testing therapies.

In today’s post, we will discuss what alpha synuclein is, explain which form of the protein was disrupted in this mouse model, review the results of the new study, and look at how tetramer stablising drugs could be a new area of PD therapeutics.

 

The 337 metre (1,106 ft) long USS Gerald R. Ford. Source: Wikipedia

Imagine you and I are standing in front of the world’s largest aircraft carrier, the USS Gerald R. Ford.

It is a VAST warship – measuring in at 337 metres (1,106 ft) in length, 76 metres (250 feet) in height – and it is a wonder of engineering composed of over a billion individual components.

And as we are standing there, gazing up at this amazing machine, I turn to you and put a nut & bolt into the palm of your hand.

A nut and bolt. Source: Atechleader

You look down at it for a moment, then turn to me, puzzled.

And that is when I say: “I would like you to find (without aid/instructions) where on this ship versions of this particular type of nut and bolt live, and try to determine exactly what functions they have“.

Where would you even start?

What tools would you use for the job? Considering the size and complexity of the vessel, would you simply give up before even starting?

It sounds like a ridiculously daunting task, but this is in effect what neurobiologists are trying to do with their study of the  brain. They start with a protein – one of the functional pieces of machinery inside each cell of our body – and then try to determine where in the brain it lives (the easy part) and what it does exactly (the REALLY hard part – most proteins have multiple functions and different configurations).

A good example of this is the Parkinson’s-associated protein alpha synuclein:

 

Alpha synuclein. Source: Wikipedia

Alpha synuclein is one of the most abundant proteins in our brains – making up about 1% of all the proteins floating around in each neuron in your head – and it is a very well studied protein (with over 9700 research reports listed on the Pubmed search engine with the key words ‘alpha synuclein’).

But here’s the thing: we are not entirely clear on what alpha synuclein actually does inside the cell. 

Que? 

In fact, biologists are not even sure about what the ‘native’ form of alpha synuclein is!

What do you mean?

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