Tagged: Substantia nigra

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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Voyager Therapeutics: Phase I clinical trial update

Today biotech company Voyager Therapeutics announced an update on their ongoing phase Ib clinical trial. The trial is evaluating the safety and tolerance of a gene therapy approach for people with advanced Parkinson’s.

Gene therapy is a technique that involves inserting new DNA into a cell using viruses. In this clinical trial, the virally delivered DNA helps the infected cell to produce dopamine in order to alleviate the motor features of Parkinson’s.

In today’s post we will discuss what gene therapy is, review the new results mentioned in the update, and look at other gene therapy approaches for Parkinson’s.



Source: Baltimoresun

Voyager Therapeutics is a clinical-stage gene therapy company that is focused on treatments for neurological conditions, such as Parkinson’s. Today the company announced an update of their ongoing Phase 1b trial of their product VY-AADC01 (Click here to see the press release).

VY-AADC01 represents a new class of treatment for Parkinson’s, as it is a form of gene therapy.

What is gene therapy?

The gene therapy involves introducing a piece of DNA into a cell which will cause the cell to produce proteins that they usually do not (either by nature or by mutation). The DNA is artificially inserted into cells and the cell’s protein producing machinery does the rest.

Source: Yourgenome

How does gene therapy work?

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Mickey becomes more human?

For a long time researchers have lacked truly disease-relevant models of Parkinson’s.

We have loaded cells with toxins to cause cell death, we have loaded cells with mutant proteins to cause cell death, we have loaded cells with… well, you get the idea. Long story short though, we have never had proper models of Parkinson’s – that is a model which present all of the cardinal features of the condition (Lewy bodies, cell loss, and motor impairment).

The various models we have available have provided us with a wealth of knowledge about the biology of how cells die and how we can protect them, which has led to numerous experimental drugs being tested in the clinic. But there has always been a linger question of ‘how disease-relevant are these models?’

This situation may be about to change.

In today’s post we will look at new research in which Japanese researchers have genetically engineered mice in which they observed the generation of Lewy bodies, the loss of dopamine neurons and motor impairments. We will look at how these mice have been generated, and what it may tell us about Parkinson’s.


Walt Disney. Source: PBS

Ok, before we start today’s post: Five interesting facts about the animator Walt Disney (1901 – 1966):

  • Disney dropped out of high school at age 16 with the goal of joining the Army to help out in the war effort. He was rejected for being underage, but was able to get a job as an ambulance driver with the Red Cross in France.
  • From 1928 (the birth of Mickey Mouse) until 1947, Disney himself performed the voice of Mickey.
  • Mickey Mouse was originally named “Mortimer Mouse”, but it was Disney’s wife who suggested that the name Mortimer sounded too pompous (seriously, can you imagine a world with the “Mortimer Mouse show”?). She convinced Disney to change the name to Mickey (the name Mortimer was later given to one of Mickey’s rivals).
  • To this day, Disney holds the record for the most individual Academy Awards and nominations. Between 1932 and 1969, he won 22 Academy Awards and was nominated 59 times (Source).
  • And best of all: On his deathbed as he lay dying from lung cancer, Disney wrote the name “Kurt Russell” on a piece of paper. They were in effect his ‘last words’. But no one knows what they mean. Even Kurt is a bit perplexed by it all. He (along with many others) was a child actor contracted to the Disney company at the time, but why did Walt write Russell’s name as opposed to something more deep and meaningful (no disrespect intended towards Mr Russell).

Actor Kurt Russell. Source: Fxguide

When asked why he thought his great creation “Mickey mouse” was so popular, Walt Disney responded that “When people laugh at Mickey Mouse, it’s because he’s so human; and that is the secret of his popularity”.

Mickey Mouse. Source: Ohmy.Disney

This is a curious statement.

Curious because in biomedical research, mice are used in experiments to better understand the molecular pathways underlying basic biology and for the testing of novel therapeutics, and yet they are so NOT human.

There are major biological differences between us and them.

Not human. Source: USNews

It has been a major dilemma for the research community for some time with regards to translating novel therapies to humans, and it raises obvious ethical questions of whether we should be using mice at all for the basic research if they are so different from us. This problem is particularly apparent in the field of immunology, where the differences between ‘mice and men’ is so vast in some cases that researcher have called for moving away from mice entirely and focusing on solely human models (Click here and here for a good reads on this topic).

What does this have to do with Parkinson’s?

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When the zombies are all in your head

In your brain there are different types of cells.

Firstly there are the neurons (the prima donnas that we believe do most of the communication of information). Next there are the microglia cells, which act as the first and main line of active immune defence in the brain. There are also oligodendrocyte, that wrap protective sheets around the branches of the neurons and help them to pass signals.

And then there are astrocytes.

These are the ‘helper cells’ which maintain a comfortable environment for the neurons and aid them in their task. Recently, researchers in California reported an curious observation in the Parkinsonian brain: some astrocytes have entered an altered ‘zombie’-like state. And this might not be such a good thing.

In today’s post, we’ll review the research and discuss what it could mean – if independently replicated – for the Parkinson’s community.


Zombies. Source: wallpapersbrowse

I don’t understand the current fascination with zombies.

There are books, movies, television shows, video games. All dealing with the popular idea of dead bodies wandering the Earth terrifying people. But why the fascination? Why does this idea have such appeal to a wide portion of the populous?

I just don’t get it.

Even more of a mystery, however, is where the modern idea of the ‘zombie’ actually came from originally.

You see, no one really knows.

Huh? What do you mean?

Some people believe that the word ‘zombie’ is derived from West African languages – ndzumbi means ‘corpse’ in the Mitsogo language of Gabon, and nzambi means the ‘spirit of a dead person’ in the Kongo language. But how did a word from the African continent become embedded in our psyche?

Others associate the idea of a zombie with Haitian slaves in the 1700s who believed that dying would let them return back to lan guinée (African Guinea) in a kind of afterlife. But apparently that freedom did not apply to situations of suicide. Rather, those who took their own life would be condemned to walk the Hispaniola plantations for eternity as an undead slave. Perhaps this was the starting point for the ‘zombie’.

More recently the word ‘zonbi’ (not a typo) appeared in the Louisiana Creole and the Haitian Creole and represented a person who is killed and was then brought to life without speech or free will.

Delightful stuff for the start of a post on Parkinson’s research, huh?

But we’re going somewhere with this.

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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).

d1ea3d21c36935b85043b3b53f2edb1f87ab7fa6

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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“Three hellos” for Parkinson’s

Trehalose is a small molecule – nutritionally equivalent to glucose – that helps to prevent protein from aggregating (that is, clustering together in a bad way).

Parkinson’s disease is a neurodegenerative condition that is characterised by protein aggregating, or clustering together in a bad way.

Is anyone else thinking what I’m thinking?

In today’s post we will look at what trelahose is, review some of the research has been done in the context of Parkinson’s disease, and discuss how we should be thinking about assessing this molecule clinically.


Neuropathologists examining a section of brain tissue. Source: Imperial

When a neuropathologist makes an examination of the brain of a person who passed away with Parkinson’s, there are two characteristic hallmarks that they will be looking for in order to provide a definitively postmortem diagnosis of the condition:

1.  The loss of dopamine producing neurons in a region of the brain called the substantia nigra.

d1ea3d21c36935b85043b3b53f2edb1f87ab7fa6

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

2.  The clustering (or ‘aggregation’) of a protein called alpha synuclein. Specifically, they will be looking for dense circular aggregates of the protein within cells, which are referred to as Lewy bodies.

A Lewy body inside of a neuron. Source: Neuropathology-web

Alpha-synuclein is actually a very common protein in the brain – it makes up about 1% of the material in neurons (and understand that there are thousands of different proteins in a cell, thus 1% is a huge portion). For some reason, however, in Parkinson’s disease this protein starts to aggregate and ultimately forms into Lewy bodies:

shutterstock_227273575

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

In addition to Lewy bodies, the neuropathologist may also see alpha synuclein clustering in other parts of affected cells. For example, aggregated alpha synuclein can be seen in the branches of cells (these clusterings are called ‘Lewy neurites‘ – see the image below where alpha synuclein has been stained brown on a section of brain from a person with Parkinson’s disease.

Lewy_neurites_alpha_synuclein

Examples of Lewy neurites (indicated by arrows). Source: Wikimedia

Given these two distinctive features of the Parkinsonian brain (the loss of dopamine neurons and the aggregation of alpha synuclein), a great deal of research has focused on A.) neuroprotective agents to protect the remaining dopamine-producing neurons in the substantia nigra, and B.) compounds that stop the aggregation of alpha synuclein.

In today’s post, we will look at the research that has been conducted on one particular compounds that appears to stop the aggregation of alpha synuclein.

It is call Trehalose (pronounces ‘tray-hellos’).

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Are we getting NURR to the end of Parkinson’s disease?

Nuclear receptor related 1 protein (or NURR1) is a protein that is critical to the development and survival of dopamine neurons – the cells in the brain that are affected in Parkinson’s disease.

Given the importance of this protein for the survival of these cells, a lot of research has been conducted on finding activators of NURR1.

In today’s post we will look at this research, discuss the results, and consider issues with regards to using these activators in Parkinson’s disease.


Comet Hale–Bopp. Source: Physics.smu.edu

Back in 1997, 10 days after Comet Hale–Bopp passed perihelion (April 1, 1997 – no joke; perihelion being the the point in the orbit of a comet when it is nearest to the sun) and just two days before golfer Tiger Woods won his first Masters Tournament, 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.

Dopamine neurons are one group of cells in the brain that are severely affected by Parkinson’s disease. 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 and the other from a person who passed away with Parkinson’s demonstrating a reduction in this cell population.

d1ea3d21c36935b85043b3b53f2edb1f87ab7fa6

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

The researchers in Sweden had made an amazing discovery – they had identified a single gene that was critical to the survival of dopamine neurons. When they artificially mutated the section of DNA where this gene lives – an action which resulted in no protein for this gene being produced – they generated genetically engineered mice with no 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 research groups (Click here and here to see examples)

So what was this amazing gene called?

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Voyager Therapeutics: phase Ib clinical trial results

 

This week a biotech company called Voyager Therapeutics announced the results of their ongoing phase Ib clinical trial. The trial is investigating a gene therapy approach for people with severe Parkinson’s disease.

Gene therapy is a technique that involves inserting new DNA into a cell using a virus. The DNA can help the cell to produce beneficial proteins that go on help to alleviate the motor features of Parkinson’s disease.

In today’s post we will discuss gene therapy, review the new results and consider what they mean for the Parkinson’s community.


Source: Joshworth

On 25th August 2012, the Voyager 1 space craft became the first human-made object to exit our solar system.

After 35 years and 11 billion miles of travel, this explorer has finally left the heliosphere (which encompasses our solar system) and it has crossed into the a region of space called the heliosheath – the boundary area that separates our solar system from interstellar space. Next stop on the journey of Voyager 1 will be the Oort cloud, which it will reach in approximately 300 years and it will take the tiny craft about 30,000 years to pass through it.

Where is Voyager 1? Source: Tampabay

Where is Voyager actually going? Well, eventually it will pass within 1 light year of a star called AC +79 3888 (also known as Gliese 445), which lies 17.6 light-years from Earth. It will achieve this goal on a Tuesday afternoon in 40,000 years time.

Gliese 445 (circled). Source: Wikipedia

Remarkably, the Gliese 445 star itself is actually coming towards us. Rather rapidly as well. It is approaching with a current velocity of 119 km/sec – nearly 7 times as fast as Voyager 1 is travelling towards it (the current speed of the craft is 38,000 mph (61,000 km/h).

Interesting, but what does any of that have to do with Parkinson’s disease?

Well closer to home, another ‘Voyager’ is also ‘going boldly where no man has gone before’ (sort of).

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Dementia with Lewy Bodies: New recommendations

jnnp-2015-January-86-1-50-F1.large

Last year – two years after actor Robin Williams died – his wife Susan Schneider Williams wrote an essay entitled The terrorist inside my husband’s head, published in the journal Neurology.

It is a heartfelt/heartbreaking insight into the actor’s final years. It also highlights the plight of many who are diagnosed with Parkinson’s disease, but experience an array of additional symptoms that leave them feeling that something else is actually wrong.

Today’s post is all about Dementia with Lewy bodies (or DLB). In particular, we will review the latest refinements and recommendations of the Dementia with Lewy Bodies Consortium, regarding the clinical and pathologic diagnosis of DLB.


robin-williams

Robin Williams. Source: Quotesgram

On the 28th May of 2014, the actor Robin Williams was diagnosed with Parkinson’s disease.

At the time, he had a slight tremor in his left hand, a slow shuffling gait and mask-like face – some of the classical features of Parkinson’s disease.

According to his wife, the diagnosis gave the symptoms Robin had been experiencing a name. And this brought her a sense of relief and comfort. Now they could do something about the problem. Better to know what you are dealing with rather than be left unsure and asking questions.

But Mr Williams sensed that something else was wrong, and he was left unsure and asking questions. While filming the movie Night at the Museum 3, Williams experienced panic attacks and regularly forgot his lines. He kept asking the doctors “Do I have Alzheimer’s? Dementia? Am I schizophrenic?”

Williams took his own life on the 11th August 2014, and the world mourned the tragic loss of a uniquely talented performer.

Source: WSJ

When the autopsy report came back from the coroner, however, it indicated that the actor had been misdiagnosed.

He didn’t have Parkinson’s disease.

What he actually had was Dementia with Lewy bodies (or DLB).

What is Dementia with Lewy bodies?

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The autoimmunity of Parkinson’s disease?

Auto

In this post we discuss several recently published research reports suggesting that Parkinson’s disease may be an autoimmune condition. “Autoimmunity” occurs when the defence system of the body starts attacks the body itself.

This new research does not explain what causes of Parkinson’s disease, but it could explain why certain brain cells are being lost in some people with Parkinson’s disease. And such information could point us towards novel therapeutic strategies.


Nature_cover,_November_4,_1869

The first issue of Nature. Source: SimpleWikipedia

The journal Nature was first published on 4th November 1869, by Alexander MacMillan. It hoped to “provide cultivated readers with an accessible forum for reading about advances in scientific knowledge.” It has subsequently become one of the most prestigious scientific journals in the world, with an online readership of approximately 3 million unique readers per month (almost as much as we have here at the SoPD).

Each Wednesday afternoon, researchers around the world await the weekly outpouring of new research from Nature. And this week a research report was published in Nature that could be big for the world of Parkinson’s disease. Really big!

On the 21st June, this report was published:

Nature
Title: T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Authors: Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A
Journal: Nature. 2017 Jun 21. doi: 10.1038/nature22815.
PMID: 28636593

In their study, the investigators collected blood samples from 67 people with Parkinson’s disease and from 36 healthy patients (which were used as control samples). They then exposed the blood samples to fragments of proteins found in brain cells, including fragments of alpha synuclein – this is the protein that is so closely associated with Parkinson’s disease (it makes regular appearances on this blog).

What happened next was rather startling: the blood from the Parkinson’s patients had a strong reaction to two specific fragments of alpha synuclein, while the blood from the control subjects hardly reacted at all to these fragments.

In the image below, you will see the fragments listed along the bottom of the graph (protein fragments are labelled with combinations of alphabetical letters). The grey band on the plot indicates the two fragments that elicited a strong reaction from the blood cells – note the number of black dots (indicating PD samples) within the band, compared to the number of white dots (control samples). The numbers on the left side of the graph indicate the number of reacting cells per 100,000 blood cells.

Table1

Source: Nature

The investigators concluded from this experiment that these alpha synuclein fragments may be acting as antigenic epitopes, which would drive immune responses in people with Parkinson’s disease and they decided to investigate this further.

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