Novel therapeutic interventions are being proposed for Parkinson’s on a regular basis, with compelling data supporting their future development.
The case is strengthened when a measure of target engagement is also involved – providing not only a potential therapy but also a biomarker as well.
Recently, a biotech company called AcureX Therapeutics has been presenting just such a case, based on a biological mechanism involving the protein Miro1.
In today’s post, we will discuss what Miro1 is and how it might be useful for future clinical trials.
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Watching the recent Michael J Fox Foundation‘s Progress in the PD Pipeline webinar (Wednesday 10th November, 2021), I was really impressed by the presentation by Dr Bill Shrader (co-founder and CEO/CSO of AcureX Therapeutics)
In particular, I really liked their approach to potential patient selection for future clinical trials of their lead drug candidate. It all revolves around the analysis of Miro1 as a biomarker.
Cellular activity generates a lot of waste and by-products. Cells have developed very efficient methods of dealing with this situation.
As we age, however, these processes become strained, and in degenerative conditions they appear to be rather dysfunctional.
New research highlights a novel mechanism – Bach1 derepression – which points towards a new class of potential therapeutics and interesting avenues of further study.
In today’s post, we will discuss the results of this new research and explore the implications of it.
I am marveling at the fact that I am typing these words.
And that you are reading them.
Consider for a moment the requirements of this arrangement. And I’m not talking about the tiny muscles changing the size of the pupil in your eye, or the neurons in your visual cortex firing in unison to give you a correct and colour-rich representation of the world in front of you that has nothing to do with the actual content being observed.
Rather, I’m thinking more about about what is going on one level down – actually inside of each cell:
There is a universe of frenzied molecular activity in each and every cell of our bodies. And we are only just starting to build up a user guide to the densely packed, fuzzy complexity of this inner world. This video gives an extremely simplified version of some of what is going on (in reality, the interior of cells is significantly more densely packed and the activity is a vastly quicker):
And as I suggested above it should be celebrated that what occurs in these cells is so rapid, efficient and precise that I can type these words and you can read them.
All of this crazy activity, however, produces waste and by-products.
Cells have of course developed very effective means of dealing with those issues. But as we age, cells can start to struggle with the task of waste disposal. And as a result, we can start to see an accumulation of these by-products, which can lead to stress on the cell, particularly in the form of oxidative stress.
For a long time it was been reported that coffee may be able to reduce the risk of developing Parkinson’s, but the mechansim by which this association could be occurring has remained elusive.
Now researchers from South Korea have discovered a biological pathway that could help to explain the protective association.
It involves a protein called PARP and a chemical called chlorogenic acid.
In today’s post, we will explore the research suggesting a link between coffee and a lower risk of Parkinson’s, discuss what PARP and chlorogenic acid are, and review the new research that may bring all four topics together.
Legend has it that in 800AD, a young Ethiopian goat herder named Kaldi noticed that his animals were “dancing”.
They had been eating some berries from a tree that Kaldi did not recognise, but being a plucky young fellow – and being fascinated by the merry behaviour of his four-legged friends – Kaldi naturally decided to self-experiment by eating some of the berries for himself.
The result?
He became “the happiest herder in happy Arabia” (Source).
This amusing encounter was apparently how humans discovered coffee. It is most likely a fiction as the earliest credible accounts of coffee-consumption emerge from the 15th century in the Sufi shrines of Yemen, but since then coffee has gone on to become one of the most popular drinks in the world.
Inflammation is the means by which tissue in our bodies communicate with the immune system to indicate when something is wrong. Tiny messenger proteins are released from stressed or damaged cells to alert neighbouring cells of their situation.
Ailing cells can also release additional components – such as DNA – that can activate immune cells and cause inflamation.
Recently, researchers have identified both messenger proteins and specific types of DNA that are present in the blood of individuals with a genetically-associated sub-type of Parkinson’s. The discovery could provide both novel biomarkers, but also point towards specific biological pathways that could be therapeutically targetted.
In today’s post, we will review this new research.
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Ouch! Source: MedicalExpress
When cells in your body are stressed, damaged, or sick, they begin to release large amounts of tiny messenger proteins which inform the rest of your body that something is wrong.
When enough of these messenger proteins are released, cells of the immune system will become activated, and come looking for the source of the trouble.
Inflammation is a critical part of the immune system’s response to problems. It is the body’s way of communicating with the immune system and explaining that something is wrong. This also aid in activating the immune system so that it can help deal with the situation.
By releasing the messenger proteins (called cytokines), injured/sick cells kick off a process that results in multiple types of immune cells entering the troubled area of the body and undertaking very specific tasks.
The strength of the immune response depends on the volume of the signal arising from those released messenger proteins.
For a long time, it has been hoped that some of these messenger proteins might be useful as biomarkers for conditions like Parkinson’s. And recently, researchers have published data suggesting that they might have found one cytokine that could be very useful for a specific sub-set of people with Parkinson’s.
Stanford University researchers have recently published an interesting report in which they not only propose a novel biomarker for Parkinson’s, but also provide some compelling data for a novel therapeutic approach.
Their research focuses on a protein called Miro, which is involved in the removal of old or faulty mitochondria. Mitochondria are the power stations of each cells, providing cells with the energy they require to do what they do.
Specifically, the researchers found that Miro refuses to let go of mitochndria in people with Parkinson’s (which could act as a biomarker for the condition). They also found that pharmacologically forcing Miro to let go, resulted in neuroprotective benefits in models of Parkinson’s
In today’s post, we will discuss what Miro is, what the results of the new research suggest, and we will consider what will happen next.
Every now and then a research report comes along and you think: “Whoa, that’s amazing!”
It a piece of work that breaks down your cynicism (which you have proudly built up over years of failed experiments) and disciplined scepticism (a critical ingredient for a career in scientific research – mantra: ‘question everything’). And for a moment you are taken in by the remarkable beauty of not just good research, but biology itself.
A couple of weeks ago, one such research report was published.
This is it here:
Title: Miro1 Marks Parkinson’s Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson’s Models. Authors: Hsieh CH, Li L, Vanhauwaert R, Nguyen KT, Davis MD, Bu G, Wszolek ZK, Wang X. Journal: Cell Metab. 2019 Sep 23. [Epub ahead of print] PMID:31564441
It’s a really interesting study for several reasons.
Today’s post is a recap of Day 3 – the final day – at the World Parkinson’s Congress meeting in Kyoto, Japan.
I will highlight some of the presentations I was able to catch and try to reflect on what was an amazing meeting.
The final day of the WPC meeting for me started with Parkinson’s advocate Heather Kennedy‘s presentation on “Your radical new life: Creative ways to overcome our challenges”. In her talk, she spoke of the mindset that is required for tackling Parkinson’s and provided some advice on what-to-do and what-not-to-do.
And Heather was speaking from personal experience. Having been diagnosed in 2012, she has become an active advocate, supporter of Davis Phinney and Michael J Fox Foundations, and an administrator on several online sites. And she regularly speaks about different methods for overcoming the challenges of Parkinson’s:
“It is not ‘why is this happening to me?’, it is ‘what is this teaching me?”
Here is a presenation she gave at the recent Parkinson’s Eve meeting in the UK earlier this year:
Key among her pieces of advice is the need to make connections:
Recently some researchers conducted an analysis of some postmortem brains from people with Parkinson’s and they discovered something rather curious.
Half of the brains that they analysed came from people with Parkinson’s who had been given deep brain stimulation (or DBS) to help manage their symptoms. When the researchers analysed the mitochondria – the powerstations of each cell – in the dopamine neurons of these brain, they found that the DBS treatment had helped to improve the number of mitochondria in these cells.
Specifically, the DBS treatment “seemed to have inhibited or reversed the reduction in mitochondrial volume and numbers” that was observed in the Parkinson’s brains that had not had DBS.
In today’s post, we will look at what DBS is, what the new research report found, and what these new findings could mean for the Parkinson’s community.
Do you know the worst thing that happens to us in life?
We wake up each day.
Every day of our lives (so far) we have woken up and been given – without any kind of justification – another 16 or so hours to do whatever we want with.
Regardless of one’s physical/mental state, this is a bad thing.
This continuous pattern is what is referred to in psychology as a ‘continuous schedule of reinforcement’. Such regimes instill complacency and – worse – expectation. They quickly lead to people taking things for granted. All of us are guilty of thinking “I’ll do it tomorrow”.
Such a continuous pattern of reinforcement does not prepare one well for a life in scientific research, where there isn’t a constant schedule of reinforcement (quite the opposite actually). Experiments regularly go wrong (reagents/equipment fail), grants/manuscripts get rejected – it can be rather brutal.
But here is where the addictive component of science comes into effect. Every so often, something works. And even better, every so often something unexpected happens – an ‘intermittent/irregular schedule of reinforcement’. An experiment will occasionally spit out a completely unexpected result, which could change everything.
These are the moments of insights that researchers are slaving for. The instant that they are the first to “walk on the moon”.
They are moments to savour.
And this must have been the state of mind for some researchers who dicovered something surprising and absolutely remarkable recently while they were looking at some postmortem brains from individuals with Parkinson’s who had been treated with deep brain stimulation.
Today we received word of a new clinical trial for Parkinson’s being initiated here in the UK. This trial – named the UP study – will evaluate the safety and tolerability of a compound called Ursodeoxycholic acid (or UDCA – click here to read the press release).
UDCA is clinically available medication that is used in the treatment of gall stone, but recently there has been a large body of research suggesting that this compound may also have beneficial effects in Parkinson’s.
In today’s post, we will look at what UDCA is, discuss the preclinical research exploring UDCA, and outline the structure of the new clinical trial.
It is one of the less appreciated organs. A pear-shaped, hollow organ located just under your liver and on the right side of your body. Its primary function is to store and concentrate your bile. What is bile you ask? Bile is a yellow-brown digestive enzyme – made and released by the liver – which helps with the digestion of fats in your small intestine (the duodenum).
One of the down sides of having a gall bladder: gallstones.
Gallstones are hardened deposits that can form in your gallbladder. About 80% of gallstones are made of cholesterol. The remaining 20% of gallstones are made of calcium salts and bilirubin. Bilirubin is the yellow pigment in bile. When the body produces too much Bilirubin or cholesterol, gallstones can develop.
About 10-20% of the population have gallstones (Source), but the vast majority experience no symptoms and need no treatment.
Interesting intro, but what does any of this have to do with Parkinson’s or a new clinical trial?
One of the treatments for gallstones is called UDCA. And today we found out that this compound is being clinically tested for “repurposing” as a treatment for Parkinson’s.
In December of of 2017, the results of a clinical trial suggested that a particular kind of exercise may have beneficial effects against certain aspects of Parkinson’s. Specifically, a high-intensity treadmill regime was found to be ‘non-futile’ as an intervention for the motor symptoms in de novo (newly diagnosed) Parkinson’s.
Recently, however, new pre-clinical research has been published which reported that when mice with particular Parkinson’s-associated genetic mutations are exercised to exhaustion, they have high levels of inflammation which can exaggerate the neurodegeneration associated with that model of PD.
So naturally, some readers are now asking “So should I be exercising or not?!?”
In today’s post we will review the results of the two studies mentioned above, and discuss why exercise is still important for people with Parkinson’s.
Readers are recommended to click on the image above and listen to the music (Michael Sembello’s “Maniac” from 1983) whilst reading this post.
This song was made famous by one particular scene from the 1983 movie “Flashdance” starring Jennifer Beals, in which the lead character undertook an intense dance routine. Ever since that iconic scene, exercise fanatics have long used the music to help get themselves into the mood for their workouts.
Nuclear factor erythroid 2–related factor 2 (or NRF2) is a protein in each of your cells that plays a major role in regulating resistance to stress. As a result of this function, NRF2 is also the target of a lot of research focused on neuroprotection.
A group of researchers from the University of British Columbia have recently published interesting findings that point towards to a biological pathway that could help us to better harness the beneficial effects of NRF2 in Parkinson’s.
In today’s post, we will discuss what NRF2 is, what the new research suggests, and how we could potentially make use of this new information.
“Oxidation nibbles more slowly – more delicately, like a tortoise – at the world around us, without a flame, we call it rust and we sometimes scarcely notice as it goes about its business consuming everything from hairpins to whole civilizations”
And he was right on the money.
Oxidation is the loss of electrons from a molecule, which in turn destabilises that particular molecule. It is a process that is going on all around us – even within us.
Iron rusting is the example that is usually used to explain oxidation. Rust is the oxidation of iron – in the presence of oxygen and water, iron molecules will lose electrons over time. And given enough time, this results in the complete break down of objects made of iron.
The combustion process of fire is another example, albeit a very rapid form of oxidation.
Oxidation is one half of a process called Redox – the other half being reduction (which involves the gaining of electrons).
Now it is important to understand, that oxidation also occurs in biology.
Molecules in your body go through the same process of losing electrons and becoming unstable. This chemical reaction leads to the production of what we call free radicals, which can then go on to damage cells.
The Science of Parkinson's 