Tagged: alpha synuclein

When undruggable becomes druggable

 

Nuclear receptor related 1 protein (or NURR1) is a protein that has been shown to have a powerful effect on the survival of dopamine neurons – a population of cells in the brain that is severely affected by Parkinson’s.

For a long time researchers have been searching for compounds that would activate NURR1, but the vast majority of those efforts have been unsuccessful, leaving some scientists suggesting that NURR1 is “undruggable” (meaning there is no drug that can activate it).

Recently, however, a research report was published which suggests this “undruggable” protein is druggable, and the activator is derived from a curious source: dopamine

In today’s post, we will discuss what NURR1 is, what the new research suggests, and how this new research could be useful in the development of novel therapeutics for Parkinson’s.

 


Source: PPcorn

It always seems impossible until it’s done – Nelson Mandela

In 1997, when Nelson Mandela was stepping down as President of the African National Congress, some researchers in Stockholm (Sweden) published the results of a study that would have a major impact on our understanding of how to keep dopamine neurons alive.

(Yeah, I know. That is a strange segway, but some of my recent intros have dragged on a bit – so let’s just get down to business)

Dopamine neurons are of the one groups of cells in the brain that are severely affected by Parkinson’s. By the time a person begins to exhibit the movement symptoms of the condition, they will have lost 40-60% of the dopamine neurons in a region called the substantia nigra. In the image below, there are two sections of brain – cut on a horizontal plane through the midbrain at the level of the substantia nigra – one displaying a normal compliment of dopamine neurons (on the left) and the other from a person who passed away with Parkinson’s demonstrating a reduction in this cell population (on the right).

The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinsonian brain (right). Source:Memorangapp

The researchers in Sweden had made an amazing discovery – they had identified a single gene (a specific region of DNA) that was critical to the survival of dopamine neurons. When they artificially disrupted the section of DNA where this gene lives – an action which resulted in no protein for this gene being produced – it resulted in mice being born with no midbrain dopamine neurons:

Title: Dopamine neuron agenesis in Nurr1-deficient mice
Authors: Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T.
Journal: Science. 1997 Apr 11;276(5310):248-50.
PMID: 9092472

The researchers who conducted this study found that the mice with no NURR1 protein exhibited very little movement and did not survive long after birth. And this result was very quickly replicated by other independent research groups (Click here and here to see examples)

So what was this amazing gene called?

Nuclear receptor related 1 protein (or NURR1; it is also known as NR4A2 – nuclear receptor subfamily 4, group A, member 2)

And what is NURR1?

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Distinctly human?

 

It is often said that Parkinson’s is a ‘distinctly human’ condition. Researchers will write in their reports that other animals do not naturally develop the features of the condition, even at late stages of life.

But how true is this statement?

Recently, some research has been published which brings into question this idea.

In today’s post, we will review these new findings and discuss how they may provide us with a means of testing both novel disease modifying therapies AND our very notion of what Parkinson’s means.

 


Checking his Tinder account? Source: LSE

Deep philosphical question: What makes humans unique?

Seriously, what differentiates us from other members of the animal kingdom?

Some researchers suggest that our tendency to wear clothes is a uniquely human trait.

The clothes we wear make us distinct. Source: Si-ta

But this is certainly not specific to us. While humans dress up to ‘stand out’ in a crowd, there are many species of animals that dress up to hide themselves from both predator and prey.

A good example of this is the ‘decorator crab’ (Naxia tumida; common name Little seaweed crab). These creatures spend a great deal of time dressing up, by sticking stuff (think plants and even some sedentary animals) to their exoskeleton in order to better blend into their environment. Here is a good example:

Many different kinds of insects also dress themselves up, such as Chrysopidae larva:

Dressed for success. Source: Bogleech

In fact, for most of the examples that people propose for “human unique” traits (for example, syntax, art, empathy), mother nature provides many counters (Humpback whales, bower birds, chickens – respectively).

So why is it that we think Parkinson’s is any different?

Wait a minute. Are there other animals that get Parkinson’s?

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Bac to the future


Over the last few years, there has been a growing body of research – and tremendous interest – focused on the role/influence of the gastrointestinal system in Parkinson’s.

In today’s post we are going to look at a recent piece of research that suggests some of the bacteria in our gut can influence the availability of the medication we use to treat Parkinson’s. 

In addition, we will look at a novel way researchers are re-engineering bacteria in the gut to correct other medical conditions (such as phenylketonuria) and we will ask if the same can not be applied to Parkinson’s.

 


The Platypus. Source: National geographic

The interesting, but utterly useless fact of the day: The duck-billed Platypus of Australia does not have a stomach.

What?

No really. These oddities of evolution have no stomach. There’s no sac in the middle of their bodies that secrete powerful acids and digestive enzymes. The oesophagus (the tube from the mouth) of the platypus connects directly to its intestines.

The platypus. Source: Topimage

And believe it or not, platypus are not alone on this ‘sans estomac‘ trend. At least a 1/4 of the fish species on this planet do not have a stomach (Source).

What?!?

And this absense of the stomach isn’t even remotely weird in the animal kingdom. Some creatures don’t even have a gastrointestinal system. No mouth. No anus. No intestines. Nothing.

WHAT?!?

The giant tube worm – Riftia pachyptila – lives on the floor of the Pacific Ocean, next to hot hydrothermal vents and can tolerate extremely high levels of hydrogen sulfide (hazardous for you and I). These creatures – which can grow up to 2.4 meters (or 7+ feet) in length – have no gastrointestinal tract whatsoever. Zip, zero, nada.

Rather they have an internal cavity – called a trophosome – filled with bacteria which live symbiotically with them.

Watch this video of Ed Yong explaining it all (great video!):

 

WOW! Fascinating! But what does ANY of this have to do with Parkinson’s?

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On your MARCKS. Get set. Go

 

An important aspect of developing better remedies for Parkinson’s involves determining when and where the condition starts in the brain. What is the underlying mechanism that kicks things off and can it be therapeutically targetted?

Recently, researchers from Japan have suggested that a protein called Myristoylated alanine-rich C-kinase substrate (or simply MARCKS) may be a potentially important player in the very early stages of Parkinson’s (and other neurodegenerative conditions).

Specifically, they have found that MARCKS is present before many of the other pathological hallmarks of Parkinson’s (such as Lewy bodies) even appear. But what does this mean? And what can we do with this information?

In today’s post, we will look at what MARCKS is, what new research suggests, and how the research community are attempting to target this protein.

 


Where does it all begin? Source: Cafi

One of the most interesting people I met during my time doing Parkinson’s assessment clinics was an ex-fire forensic investigator.

We would generally start each PD assessment session with a “brief history” of life and employment – it is a nice ice breaker to the appointment, helped to relax the individual by focusing on a familiar topic, and it could provide an indication of potential issues to consider in the context of Parkinson’s – such as job related stress or exposure to other potential risk factors (eg. pesticides, etc).

Source: Assessment

But so fascinated was I with the past emplyoment of the ex-fire forensic investigator gentleman that the “brief history” was anything but brief.

We had a long conversation.

One aspect of fire forensics that particularly fascinated me was the way he could walk into a recently burned down property, and he could “read the story backwards” to identify the root cause of the fire.

He could start anywhere on a burnt out property and find his way back to the source (and also determine if the fire was accidental or deliberate).

Where did it all start? Source: Morestina

I marvelled at this idea.

And I can remember wondering “why can’t we do that with Parkinson’s?

Well, recently some Japanese researchers have had a crack at “reading the story backwards” and they found something rather interesting.

What did they find?

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The lipidomics of Parkinson’s

 

Lipids are ‘waxy’ molecules that make up a large proportion of your brain and they play very important roles in normal brain function. For a long time researchers have also been building evidence that lipids may be involved with neurodegenerative conditions as well.

Recently, new research was presented that supports this idea (in the case of Parkinson’s at least), as two research groups published data indicating that certain lipids can influence the toxicity of the Parkinson’s associated protein alpha synuclein.

One of those research groups was a biotech company called Yumanity, and they are developing drugs that target the enzymes involved with the production of the offending lipids.

In today’s post, we will look at what lipids are, what the new research suggests, and discuss some of the issues that will need to be considered in the clinical development of these lipid enzyme inhibitors.

 


Yummy. Source: Healthline

Adherence to the ‘Mediterranean diet‘ has been associated with a reduced risk of developing Parkinson’s (Click here and here to read more about this), but no one has ever really explained why.

There has been the suggestion from some corners that this association may be due to the richness of monounsaturated fats in the foods generally included in this diet.

For example, olive oil is rich in monounsaturated fat.

What are monounsaturated fats?

Mmmm, before I answer that we need to have a broader discussion about “what is fat?“.

Fat is one of the three main macronutrients (carbohydrate and protein being the other two) that the body requires for survival.

Source: Visionpt

Fat serves as a ready source of energy for the body and can also provide insulation against cold temperatures or compression. All fats are derived from combinations of fatty acids (and also glycerol).

What are fatty acids?

A fatty acid is simply a chain of hydrocarbons terminating in a carboxyl group (having a carbonyl and hydroxyl group both linked to a carbon atom). Don’t worry too much about what that means, just understand that fatty acids are basically chains of hydrocarbons that look like this:

A chain of hydrocarbons ending in a carboxyl group (right). Source: Wikipedia

Fatty acids come in two forms:

  • Saturated
  • Unstaturated

In the case of a saturated fat, each carbon molecule in the chain of hydrocarbons is bonded to two other carbons by a single bond. Whereas in the case of a saturated fat, one or more carbon molecule in the chain of hydrocarbons is bonded to another carbon molecule by a double bond. For example:

Saturated fatty acids vs unsaturated fatty acids. Source: Medium

And unsaturated fatty acids can be further divided into:

  1. Monounsaturated fatty acids (or MUFAs) are simply fatty acids that have a single double bond in the fatty acid chain with all of the remainder carbon atoms being single-bonded.
  2. Polyunsaturated fatty acids (or PUFAs) are fatty acids that have more than one double bond.

Source: Medium

OK, but how might monounsaturated fats be involved with Parkinson’s?

That, dear reader, is the focus of numerous studies in the field of lipidomics.

What is lipidomics?

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Thyme to look east: Baicalein

 

Recently I wrote a post about research investigating an interesting compound called Epigallocatechin gallate (or EGCG – click here for that post). Several eagle-eyed readers, however, noted something interesting in the details of one of the research reports that was discussed in that post.

The study in question had used EGCG as a positive control for evaluating the ability of other compounds for their ability to inhibit the clustering of Parkinson’s-associated protein alpha synuclein.

But there was also a second positive control used in that study.

It is called baicalein.

In today’s post, we will discuss what baicalein is and what research has been done on it in the context of Parkinson’s.

 


Lake Baikal. Source: Audleytravel

Once upon a thyme, in a far away land, there was a mysterious little flowering plant.

The “far away land” was the southern parts of eastern Siberia.

And the flowering plant is Scutellaria baicalensis – which is more commonly referred to as Baikal skullcap.

What is Baikal skullcap?

Baikal skullcap is a perennial herb that is indigenous to Southern Siberia, China and Korea. For centuries, traditional Chinese medicine has used the dried roots – which is called huángqín (Chinese: 黄芩 or golden root) – for a variety of ailments.

Baikal skullcap. Source: Urbol

The plant grows to between 1-4 feet in height, with lance head-shaped leaves and blue-purple flowers. Baikal skullcap belongs to the same family of flowering plants (Lamiaceae) as thyme, basil, mint and rosemary.

For traditional Chinese medicinal use, the roots are usually collected in spring or autumn once the plant is more than 3-4 years old. They are dried and then used to treat hypertension, to reduce “fire and dampness”, and to treat prostate & breast cancers.

And one of the key constituents of Baikal skullcap (and huángqín) is a compound called baicalein.

What is baicalein?

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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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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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