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This week it was announced that Oleh Hornykiewicz had passed away.
I appreciate that most readers will not know who he is, but understand that his contribution to Parkinson’s research was important.
Not only was he instrumental in the discovery that dopamine is significantly reduced in the Parkinsonian brain, but he also demonstrated that levodopa treatment can help restore function.
In today’s post, we remember Oleh Hornykiewicz.
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It was sad to hear of the passing away of Oleh Hornykiewicz this week.
Most readers will have little clue as to who he was, but he played a very important role in the development of the Parkinson’s treatment we know of as levodopa therapy.
Very early in the 20th century, a chemical called dopamine was discovered, but no one really knew anything about it until a young Swedish research named Arvid Carlsson started to play with it.
Prof Arvid Carlsson. Source: Alchetron
In 1957, Carlsson discovered that when he injected a drug called reserpine into the brains of rabbits, the animals exhibited limited ability to move. He found that reserpine depleted levels of dopamine in the brains of the rabbits. He also discovered that by injecting the dopamine precursor – levodopa (more on this below) – into those same animals, he was able to rescue their motor ability. Importantly, he found that the precursor (called 5-hydroxytryptophan) to another chemical called serotonin, it was not capable of reversing the reduction in motor ability, indicating that the effect was specific to levodopa and dopamine.
He published this amazing result in the prestigeous scientific journal ‘Nature’:
Title: 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists.
Authors: Carlsson A, Lindqvist M, Magnusson T.
Journal: Nature. 1957 Nov 30;180(4596):1200. No abstract available.
PMID: 13483658 (the article on the Nature website – access required)
This was a fantastic discovery.
But what to do with it?
And that is where an Austrian researcher named Oleh Hornykiewicz becomes part of the story.
In the Parkinsonian brain, there is a severe reduction in a substance called dopamine. Reduced levels of this chemical are associated with the appearance of the motor features of Parkinson’s.
Dopamine replacement therapies has been the front line therapy for the condition for the last 50 years. But long-term use of drugs like L-dopa are associated with the rise of motor complications, like dyskinesias.
In the an effort to correct this, researchers in France have recently developed a method of continuously and directly delivering dopamine to the brain. They have now published the results of a study evaluating the safety and feasibility of this approach in a primate model of Parkinson’s.
In today’s post, we will discuss what dopamine is, review the results of this new research, and explore what might happen next for this new potential treatment method.
Prof David Devos. Source: Youtube
This is Dr David Devos.
He is Professor of medical pharmacology at University of Lille (France), world-renowned Parkinson’s researchers, a passionate advocate for the Parkinson’s community, and on top of all that he’s a really (and I mean REALLY) nice guy as well.
Recently, his research group (in collaboration with other scientists) published a report presenting a novel way of treating Parkinson’s, that he is now hoping to take to the clinic.
Here is the report:
Title: Intraventricular dopamine infusion alleviates motor symptoms in a primate model of Parkinson’s disease.
Authors: Moreau C, Rolland AS, Pioli E, Li Q, Odou P, Barthelemy C, Lannoy D, Demailly A, Carta N, Deramecourt V, Auger F, Kuchcinski G, Laloux C, Defebvre L, Bordet R, Duce J, Devedjian JC, Bezard E, Fisichella M, David D.
Journal: Neurobiol Dis. 2020 Mar 20:104846.
PMID: 32205254 (This report is OPEN ACCESS if you would like to read it)
In this study, the researchers wanted to explore how to directly deliver a chemical called dopamine to the brain.
What is dopamine?
Recently a really interesting research report was published that presented several rather amazing findings.
The researchers forced dopamine-producing cells in a rodent brain to start making a protein called neuromelanin and by doing this, they witnessed the occurence of Parkinson’s-like features (motor issues, Lewy body-like structures, and cell death).
The report also suggested a method by which this outcome could be reduced or rescued.
But the amazing part is that neuromelanin was previously considered to be protective and this new finding suggests we may need to rethink that idea.
In today’s post, we will discuss what neuromelanin is, what this new report found, and how this new knowledge could be useful in the context of Parkinson’s.
Prof Heiko Braak. Source – Memim.com
This is Prof Heiko Braak.
Many years ago, he sat down and examined hundreds of postmortem brains from people with Parkinson’s.
He had collected brains from people who passed away at different stages of the condition, and was looking for any kind of pattern that might explain where and how the disease starts. His research led to what is referred to as the “Braak staging” model of Parkinson’s – a six step explanation of how the condition spreads up from the brain stem (the top of the spinal cord) and into the rest of the brain (Click here and here to read more about this).
The Braak stages of PD. Source: Nature
Braak found that certain populations of cells in the brain were more vulnerable to Parkinson’s than others, such as the dopamine neurons in a region called the substantia nigra, the noradrenergic neurons of the locus coeruleus, and the neurons of the dorsal motor nucleus of the vagus (don’t worry about what any of those names actually mean, I’m just trying to sound smart and make you think that I know what I’m taking about).
One feature that all of these populations of neurons all share in common – in addition to vulnerability to Parkinson’s – is the production of pigment called neuromelanin.
What is neuromelanin?
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?
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
The good news 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:
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?
This week a biotech company called Voyager Therapeutics provided an update regarding a gene therapy approach for people with severe Parkinson’s.
Gene therapy is an experimental therapeutic approach that involves inserting new DNA into cells using a virus. The introduced DNA can help a cell to produce proteins that it usually wouldn’t produce, and this can help to alleviate the motor features of Parkinson’s.
In today’s post we will discuss what gene therapy is, what Voyager Therapeutics is trying to do, and outline what their update reported.
There are 4 phases to the clinical trial process of testing new treatment for use in humans:
- Phase I determines if a treatment is safe in humans (this is conducted in an ‘open label’ manner)
- Phase II ‘double blindly’ assesses in a small cohort of subjects if the treatment is effective
- Phase III involves randomly and blindly testing the treatment in a very large cohort of patients
- Phase IV (often called Post Marketing Surveillance Trials) are studies conducted after the treatment has been approved for clinical use
(‘Open label’ refers to both the investigator and the participants in a study knowing what treatment is being administered; while ‘double blind’ testing refers to studies in which the participants and the investigators do not know whether the participant is receiving the active treatment or an inert control treatment until the end of the study).
Based on the successful completion of their Phase I clinical trials for their gene therapy treatment called VY-AADC (Click here to read more about this), Boston-based biotech firm Voyager Therapeutics approached the US Food and Drug Administration (FDA) with the goal of shifting their clinical trial programme into Phase II testing.
What is gene therapy?
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.
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.
How does gene therapy work?
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?
“Repurposing” in medicine refers to taking drugs that are already approved for the treatment of one condition and testing them to see if they are safe and effective in treating other diseases. Given that these clinically available drugs have already been shown to be safe in humans, repurposing represents a method of rapidly acquiring new potential therapeutics for a particular condition.
The antidepressant, Trazodone, has recently been proposed for repurposing to neurodegenerative conditions, such as Parkinson’s.
In today’s post we will look at what Trazodone is, why it is being considered for repurposing, and we will review the results of a new primate study that suggests it may not be ideal for the task.
Opinions. Everyone has them. Source: Creativereview
I am regularly asked by readers to give an opinion on specific drugs and supplements.
And I usually cut and paste in my standard response: I can not answer these sorts of questions as I am just a research scientist not a clinician; and even if I was a clinician, it would be unethical for me to comment as I have no idea of your medical history.
In many of these cases, there simply isn’t much proof that the drug/supplement has any effect in Parkinson’s, so it is hard to provide any kind of “opinion”. But even if there was proof, I don’t like to give opinions.
Eleven out of every ten opinions are usually wrong (except in the head of the beholder) so why would my opinion be any better? And each individual is so different, why would one particular drug/supplement work the same for everyone?
In offering an answer to “my opinion” questions, I prefer to stick to the “Just the facts, ma’am” approach and I focus solely on the research evidence that we have available (Useless pub quiz fact: this catchphrase “Just the facts, ma’am” is often credited to Detective Joe Friday from the TV series Dragnet, and yet he never actually said it during any episode! – Source).
Detective Joe Friday. Source: Wikipedia
Now, having said all of that, there is one drug in particularly that is a regular topic of inquiry (literally, not a week goes by without someone asking about): an antidepressant called Trazodone.
What is Trazodone?
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.