Tagged: aggregate

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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EGCG: Anyone fancy a cuppa?

 

The clustering (or aggregation) of the protein, alpha synuclein, is a cardinal feature of the Parkinsonian brain, and it is believed to be associated with the neurodegeneration that characterises the condition.

As a result, many pharmaceutical and biotech companies are focused a great deal of attention on identifying novel compounds that can enter the brain and inhibit alpha synuclein from aggregating. Recently, a collaboration of companies published the results of an amazingly large study highlighting novel inhibitors.

But an interesting aspect of the results was the ‘positive control’ compound they used: Epigallocatechin Gallate (or simply EGCG)

In today’s post, we will review the results of the study, discuss what EGCG is, and look at what is known about this compound in the context of Parkinson’s.

 


Source: Cargocollective

Every now and then, the research report of a huge study comes along.

And by that, I don’t mean that the results have a major impact. Rather, I am referring to the scope and scale of the work effort required to conduct the study. For example, the GIANT study which is looking for genetic variations associated with height (Click here to read a previous SoPD post that briefly touches on that study).

Recently, the report of one huge study was published:

Title: Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State
Authors: Kurnik M, Sahin C, Andersen CB, Lorenzen N, Giehm L, Mohammad-Beigi H, Jessen CM, Pedersen JS, Christiansen G, Petersen SV, Staal R, Krishnamurthy G, Pitts K, Reinhart PH, Mulder FAA, Mente S, Hirst WD, Otzen DE.
Journal: Cell Chem Biol. 2018 Aug 29. pii: S2451-9456(18)30271-X.
PMID: 30197194

In this study, researchers from Arrhus University, Biogen, Amgen, Genentech, Forma Therapeutics, & Alentis Pharma screened almost 750,000 different compounds for their ability to interact with the Parkinsons-associated protein alpha synuclein.

And before we go any further, just take a moment to fully appreciate the size of that number again:

Source: peopleforbikes

That is eye watering stuff! That is a “I need to sit down for a moment and let this sink in” kind of number. That is a “Are there that many compounds in all of the known universe?” number.

After reading the number, I was left wondering what each of the scientists involved in this study must have been thinking when the boss first said “Hey guys, let’s screen half a million compounds…. no, wait, better yet, why stop there. Let’s make it 3/4 of a million compounds

How enthusiastic was the “Yes boss” response, I wonder?

All kidding aside, this is an amazing study (and the actual number of compounds screened was only 746,000).

And the researchers who conducted the study should be congratulated on their achievement, as the results of their study may have a profound impact in the longer-term for the Parkinson’s community – you see, the researchers found 58 compounds that markedly inhibited the aggregation of alpha synuclein, as well as another 100 compounds that actually increased its aggregation. A great deal of research will result from this single, remarkable piece of work.

But of particular interest to us here at the SoPD, was the activity of one of the positive control compounds that the researchers used in some of the tests.

What was the control compound?

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The Mannitol results

Last week the first results of an ambitious project are being shared with the Parkinson’s community.

Clinicrowd is a “crowd sourcing platform exploring disease treatments that Pharma companies have no interest to investigate or promote”. Their initial focus was Parkinson’s (though they now have additional projects for other medical conditions), and their first experimental treatment for Parkinson’s was the sweetener ‘mannitol’.

The results provide some interesting insights into the properties of mannitol and into crowd sourced projects.

In today’s post, we will discuss what mannitol is, why it is interesting, outline the Clinicrowd project, and review the results of the mannitol study.


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Mannitol. Source: Qualifirst

Without a shadow of doubt, one of the most popular topics searched for on this website is ‘mannitol’.

In 2017, the second most visited page on the site (behind only the main/home page) was a post called “Update – Mannitol and Parkinson’s“. And as if to put an exclamation point on the matter, the fourth most visited page was “Manna from heaven? Mannitol and Parkinson’s

Understand though, that both of these posts were actually written in 2016!

Throughout 2017-18, not a week has gone by without someone contacting me to ask about mannitol and the ‘CliniCrowd‘ project.

Thus, it brings me great pleasure to sit down tonight and write this post.

What is mannitol?

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A vaccine for Parkinson’s – the AFFiRiS update

This week Austrian biotech firm, AFFiRiS AG, made an announcement regarding their experimental immunotherapy/’vaccine’ approach for Parkinson’s.

In their press release, the company provided the results of a long-term Phase I clinical trial testing the tolerability and safety of their treatment AFFITOPE® PD01A.

The treatment was found to be safe and well-tolerated in people with Parkinson’s. But there was one sentence which was particularly intriguing in the press release regarding clinical symptoms.

In today’s post, we will discuss what is meant by ‘immunotherapy’, outline what this particular clinical trial involved, review the results, and explore what this could mean for the Parkinson’s community.


Source: uib

I have previously mentioned on this website that any ‘cure for Parkinson’s’ is going to require three components:

  1. A disease halting mechanism
  2. A neuroprotective agent
  3. Some form of cell replacement therapy

This week we got some interesting clinical news regarding the one of these components: A disease halting mechanism

Clinical trial results from Austria suggest that a new immunotherapy approach in people with Parkinson’s is both safe and well tolerated over long periods of time.

What is immunotherapy?

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I’ll have the fish please

We have previously discussed the importance of the right foods for people with Parkinson’s on this blog – Click here for a good example.

Recently, new data from researchers in Sweden points towards the benefits of a specific component of fish in particular.

It is a protein called β-parvalbumin, which has some very interesting properties.

In today’s post, we discuss what beta-parvalbumin is, review the new research findings, and consider how this new information could be applied to Parkinson’s.


A very old jaw bone. Source: Phys

In 2003, researchers found 34 bone fragments belonging to a single individual in a cave near Tianyuan, close to Beijing (China).

But it was not the beginning of a potential murder investigation.

No, no.

This was the start of something far more interesting.

Naming the individual “Tianyuan man”, the researchers have subsequently found that “many present-day Asians and Native Americans” are genetically related to this individual. His bones represented one of the oldest set of modern human remains ever found in the eastern Eurasia region.

Tianyuan caves. Source: Sciencemag

But beyond the enormous family tree, when researchers further explored specific details about his jaw bone (or lower mandible as it is called) they found something else that was very interesting about Tianyuan man:


Title: Stable isotope dietary analysis of the Tianyuan 1 early modern human.
Authors: Hu Y, Shang H, Tong H, Nehlich O, Liu W, Zhao C, Yu J, Wang C, Trinkaus E, Richards MP.
Journal: Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):10971-4.
PMID: 19581579                     (This research article is OPEN ACCESS if you would like to read it)

In this study, the investigators analysed the carbon and nitrogen isotopes found within bone collagen samples taken from the jaw bone of Tianyuan man. In humans, the carbon and nitrogen isotope values indicate the sources of dietary protein over many years of life.

The researchers found that a substantial portion of Tianyuan man’s diet 40,000 years ago came from freshwater fish.

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

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On the importance of Calcium

Recently researcher from the University of Cambridge reported that an imbalance in calcium and the Parkinson’s-associated protein alpha synuclein can cause the clustering of synaptic vesicles.

What does this mean? And should we reduce our calcium intake as a result?

In today’s post, we will review the research report, consider the biology behind the findings and how it could relate to Parkinson’s, and discuss what can or should be done.


Me and Brie. Source: Wikipedia

When I turned 25, I realised that my body no longer accepted cheese.

This was a very serious problem.

You see, I still really liked cheese.

A bottle of red wine, a baguette and a chunk of brie – is there any better combination in life?

So obviously my body and I had a falling out. And yes, it got ugly. I wanted things to keep going the way they had always been, so I tried to make things interesting with new and exotic kinds of cheeses, which my body didn’t want to know about it. It rejected all of my efforts. And after a while, I gradually started resenting my body for not letting me be who I was.

We sought help. We tried interventions. But sadly, nothing worked.

And then things got really bad: My body decided that it didn’t have room in its life for yogurt, milk or even ice cream anymore (not even ice cream!!!). Basically no dairy what so ever.

There’s something’s missing in my life. Source: Morellisices

OMG. How did you survive without ice cream?

Well, I’ll tell ye – it’s been rough.

All silliness aside though, here is what I know: It is actually very common to develop a lactase deficiency as we get older – lactase being the enzyme responsible for the digestion of whole milk. In fact, about 65% of the global population has a reduced ability to digest lactose after infancy (Source: NIH). I am not lactose intolerant (one of the few tests that I actually aced in my life), but I do have trouble digesting a particular component of dairy products – which can result in discomfort and socially embarrassing situations (one day over a drink I’ll tell you the ‘cheese fondue story’). Curiously, that mystery ingredient is also present in products that have no dairy (such as mayonnaise – it absolutely kills me).

But spare me your tears, if one is forced to drop a particular food group, dairy is not too bad (if I am ever forced to give up wine, I swear I’ll go postal).

My biggest concern when I dropped dairy, however, was “where was I going to get my daily requirements of calcium?“.

Understand that calcium is really rather important.

Why is calcium important?

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The aggregating antics of (some) anaesthetics

This is one of those posts that I am reluctant to write because there is the very real possibility of it being taken out of context and causing someone to panic. But several readers have asked me to address a new piece of research that was published this week which has them concerned.

Anaesthetics are very useful agents in medicine, but they have long been known to have biological effects beyond simply numbing/sedating individuals. Some of those effects are beneficial, while others….mmm, not so beneficial. And the new research published this week leans towards the latter: Certain anaesthetics apparently induce mutant protein aggregation in neurons and cause stress responses in those brain cells.

In today’s post, we will discuss what anaesthetics are, how (we think) they work, and what the results of this new research actually mean.


William Morton’s first public demonstration. Source: Pinterest

On Friday 16th October 1846, history was made.

On that date, an American dentist named William T. G. Morton (1819-1868) made the first public demonstration of the use of inhaled ether as a surgical anaesthetic.

William Morton. Source: Wikipedia

At this demonstration Dr. John Collins Warren painlessly removed a tumor from the neck of a Mr. Edward Gilbert Abbott. After finishing the operation and Abbott had regained consciousness, Warren asked Abbott how he felt.

John Collins Warren. Source: General-anaesthesia

Abbott replied, “Feels as if my neck’s been scratched.”

Warren then turned to the medical audience and said:

“Gentlemen, this is no Humbug”

This was an obvious shot at an unsuccessful demonstration of nitrous oxide as a anaesthesia the year before (by Horace Wells in the same theatre), which ended with the audience shouting “Humbug!” after they heard the patient groaning with pain during the procedure.

The important thing to appreciate here is the magnitude of Morton’s achievement within in the history of medicine.

Before 16th October 1846, surgical procedures were not very pleasant affairs.

After 16th October 1846,… well, to be honest, they are still not very pleasant affairs, but at least the patient can skip most of the painful parts of an operation.

Interesting. But what does this have to do with Parkinson’s?

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The anti-depressing research of antidepressants

Antidepressants are an important class of drugs in modern medicine, providing people with relief from the crippling effects of depression.

Recently, research has suggested that some of these drugs may also provide benefits to people suffering from Parkinson’s disease. But by saying this we are not talking about the depression that can sometimes be associated with this condition.

This new research suggests anti-depressants are actual providing neuroprotective benefits.

In today’s post we will discuss depression and its treatment, outline the recent research, and look at whether antidepressants could be useful for people with Parkinson’s disease.


Source: NatureWorldNews

It is estimated that 30 to 40% of people with Parkinson’s disease will suffer from some form of depression during the course of the condition, with 17% demonstrating major depression and 22% having minor depression (Click here to read more on this).

This is a very important issue for the Parkinson’s community.

Depression in Parkinson’s disease is associated with a variety of poor outcomes not only for the individuals, but also for their families/carers. These outcomes can include greater disability, less ability to care for oneself, faster disease progression, reduced cognitive performance, reduced adherence to treatment, worsening quality of life, and increased mortality. All of which causes higher levels of caregiver distress for those supporting the affected individual (Click here to read more about the impact of depression in early Parkinson’s).

What is depression?

Wikipedia defines depression as a “state of low mood and aversion to activity that can affect a person’s thoughts, behaviour, feelings, and sense of well-being” (Source). It is a common mental state that causes people to experience loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration.

Importantly, depression can vary significantly in severity, from simply causing a sense of melancholy to confining people to their beds.

Source: Prevention

What causes depression?

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Are Lewy bodies fake news?

One of the cardinal features of the Parkinsonian brain are dense, circular clusters of protein that we call ‘Lewy bodies’

But what exactly are these Lewy bodies?

How do they form?

And what function do they serve?

More importantly: Are they part of the problem – helping to cause of Parkinson’s? Or are they a desperate attempt by a sick cell to save itself?

In today’s post, we will have a look at new research that makes a very close inspection of Lewy bodies and finds some interesting new details that might tell us something about Parkinson’s.


Neuropathologists conducting a gross examination of a brain. Source: NBC

A definitive diagnosis of Parkinson’s disease can only be made at the postmortem stage with an examination of the brain. Until that moment, all cases of Parkinson’s disease 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).

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The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp

2.  Dense, circular clusters (or aggregates) of protein within cells, which are called Lewy bodies.

shutterstock_227273575

A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news

What is a Lewy body?

A Lewy body is referred to as a cellular inclusion (that is, ‘a thing that is included within a whole’), 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) 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

How do Lewy bodies form? And what is their function?

The short answer to these questions is:

Source: Wellbeing365

The longer answer is: Our understanding of how Lewy bodies are formed – and their actual role in neurodegenerative conditions like Parkinson’s – is extremely limited. No one has ever observed one forming. Lewy bodies are very difficult to generate in the lab under experimental conditions. And as for their function, this is the source of much guess work and serious debate (we’ll come back to this topic later in this post).

Ok, but what are Lewy bodies actually made of?

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The TAU of Parkinson’s

Here at the SoPD, we regularly talk about the ‘bad boy’ of Parkinson’s disease – a protein called Alpha Synuclein.

Twenty years ago this year, genetic variations were identified in the alpha synuclein gene that increase one’s risk of developing Parkinson’s. In addition, alpha synuclein protein was found to be present in the Lewy bodies that are found in the brains of people with Parkinson’s. Subsequently, alpha synuclein has been widely considered to be the villain in this neurodegenerative condition and it has received a lot of attention from the Parkinson’s research community.

But it is not the only protein that may be playing a role in Parkinson’s.

Today’s post is all about TAU.


Source: Wallpaperswide

I recently informed my wife that I was thinking of converting to Taoism.

She met this declaration with more of a smile than a look of shock. And I was expecting the latter, as shifting from apatheism to any form of religious belief is a bit of a leap you will appreciate.

When asked to explain myself, I suggested to her that I wanted to explore the mindfulness of what was being proposed by Lao Tzu (the supposed author of the Tao Te Ching – the founding document of Taoism).

This answer also drew a smile from her (no doubt she was thinking that Simon has done a bit of homework to make himself sound like he knows what he was talking about).

But I am genuinely curious about Taoism.

Most religions teach a philosophy and dogma which in effect defines a person. Taoism – which dates from the 4th century BCE – flips this concept on its head. It starts by teaching a single idea: The Tao (or “the way”) is indefinable. And then it follows up by suggesting that each person should discover the Tao on their own terms. Given that most people would prefer more concrete definitions in their own lives, I can appreciate that a lot of folks won’t go in for this approach.

Personally speaking, I quite like the idea that the Tao is the only principle and everything else is a just manifestation of it.

According to Taoism, salvation comes from just one source: Following the Tao.

Source: Wikipedia

Oh and don’t worry, I’m not going to force any more philosophical mumbo jumbo on you – Taoism is just an idea I am exploring as part of a terribly clichéd middle-life crisis I’m working my way through (my wife’s actual response to all of this was “why can’t you just be normal and go buy a motor bike or something?”).

My reason for sharing this, however, is that this introduction provides a convenient segway to what we are actually going to talk about in this post.

You see, some Parkinson’s researchers are thinking that salvation from neurodegenerative conditions like Parkinson’s will come from just one source: Following the TAU.

What is TAU?

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