Tag: Parkin

Getting a handle on Miro1

~ Simon ~ Leave a comment

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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.

What is Miro1?

Continue reading “Getting a handle on Miro1” →

The age-associated changes of PARKIN

~ Simon ~ 4 Comments

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Tiny variations in a region of DNA referred to as “Parkin” are associated with an increased risk of developing Parkinson’s (particularly young onset forms of the conditions). The Parkin DNA provide the instructions for making a protein that is involved with many functions inside cells.

New research indicates that as we age, Parkin protein becomes less available. In fact, by the time we turn 50 years of age, “Parkin is largely insoluble”, meaning that the majority of the protein is no longer able to do its job.

This shift appears to involve oxidation changes.

In today’s post, we will discuss what Parkin and oxidation are, how Parkin might be affected by oxidation, and how this information might be useful to treating Parkin-associated Parkinson’s.

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Me (I wish) before 27. Source: Pinterest

I don’t know about you, but 27 was my peak.

Before my 27th birthday, I could run around all over the place – acting like an idiot, with all the energy in the world. I was invincible and having lots of fun. And yes, some vices might have been involved – I would drink myself blind on a Friday night, wake up fresh the next day and do it all merrily again.

Me before 27. Source: Thefix

But then, my 27th birthday came along and I woke up the next day tired and feeling… fatigued. Weary even. And definitely with less enthusiasm than I had before I passed out the night before. My father called it a “hang-over” (which up until that time I had naively/idiotically thought I was immune to).

Me, before (left) and after 27 (right). Source: Wanna-joke

But I gradually developed this sinking feeling that it was something else.

Something more sinister.

It was as though something had changed. Something inside of me.

And I distinctly remember a moment of realisation, when I asked “Am I getting old???”

My father saw my concern and gave me sage advice (“It’s like I always say, aging ain’t for sissies“), and with that I changed my ways.

Source: DS

Since that moment, I have been fascinated by the biology of aging, particularly in the context of Parkinson’s (age is the main correlate with neurodegenerative conditions like Parkinson’s and Alzheimer’s). So it was with great interest that I read a manuscript in November last year that had been posted on the openly-available preprint database bioRxiv.

What did the manuscript say?

Continue reading “The age-associated changes of PARKIN” →

A PINK shade of inflammation

~ Simon ~ 5 Comments

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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.

This is inflammation.

Source: Youtube

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 inflammatory process. Source: Trainingcor

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.

What did they find?

Continue reading “A PINK shade of inflammation” →

Problems with PARKIN in PARIS

~ Simon ~ 2 Comments

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PARKIN is a protein that is associated with a young-onset form of Parkinson’s. Individuals carrying tiny genetic variants in the region of DNA producing this protein have a higher risk of developing Parkinson’s before the age of 40 than non-carriers.

The PARKIN protein is believed to play an important role in the disposal of old/damaged mitochondria (the power stations of cells). But recent research points towards another protein – that interacts with PARKIN – which may also be implicated in the health and well being of mitochondria.

That other protein is called PARIS.

In today’s post, we will discuss what PARKIN does, explore how PARIS could be involved, and reflect on what this could mean for future therapies targeting PARKIN-associated Parkinson’s.

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paris

No label required. A magnificent city. Source: HathawaysofHaworth

Paris is not my favourite city (Hanoi takes that spot), but it is probably in the top 10.

Like London and New York, La Ville Lumière is an incredible place to be fortunate enough to visit.

If you ever find yourself in Paris, bored of all the art, culture, food, etc, and you feel like something more scientific, make your way up the Seine river to the 5th arrondissement, and try to find the Muséum national d’histoire naturelle. Once you get there, ask for the “Galerie de Paléontologie et d’Anatomie comparée” (Paleontology and comparative Anatomy Gallery):

This is the realm of Georges Cuvier – the French paleontologist who researched fossils and in 1796 laid out the first ideas for extinction theory. It is a hall of scientific wonder.

As I say, it is worth a visit if ever you are bored in Paris. But be warned that parking is an issue at the Jardin des plantes where the gallery is located.

In fact, parking is an issue everywhere in Paris.

It seems like Parking and Paris do not mix.

I’m sorry, but what does this have to do with Parkinson’s?

Continue reading “Problems with PARKIN in PARIS” →

Putting the PARKIN back into Parkinson’s

~ Simon ~ 3 Comments

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Genetic variations in a region of our DNA called PARKIN is associated with an increased risk of developing Parkinson’s – particularly young-onset PD (diagnosed before the age of 40yrs).

This area of DNA provides the instructions for making a protein (also referred to as PARKIN), which plays a number of important roles inside of cells.

Recently, a South Korean biotech company called Cellivery has published research on an experimental therapeutic agent that easily penetrates both the brain and cells within, delivering PARKIN protein to the cells that need it.

In today’s post, we will discuss what PARKIN does, review the new research report, and explore what could happen next.

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Source: Quanta

Here on the SoPD we often talk about research regarding the prominent Parkinson’s associated proteins, think of alpha synuclein, LRRK2 and GBA. And they are of interest as there is a great deal of activity now at the clinical level exploring agents targetting these proteins.

But there are a number of interesting therapeutics being developed that are exploring some of the other Parkinson’s-associated proteins.

A good example was published this week:

Title: Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein
Authors: Chung E, Choi Y, Park J, Nah W, Park J, Jung Y, Lee J, Lee H, Park S, Hwang S, Kim S, Lee J, Min D, Jo J, Kang S, Jung M, Lee PH, Ruley HE & Jo D
Journal: Science Advances, 29 Apr 2020:6, 18, eaba1193
PMID: N/A

In this study, South Korean researchers demonstrated that a brain penetrating compound (including the PARKIN protein) can rescue numerous models of Parkinson’s.

Hang on a second: What is PARKIN?

Continue reading “Putting the PARKIN back into Parkinson’s” →

When miro just can’t let go

~ Simon ~ 20 Comments

 

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.

 

 

Source: Amazingaccelerators

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.

So what did they report?

Continue reading “When miro just can’t let go” →

A re-think of PINK

~ Simon ~ 7 Comments

 

The immune system is our main line of defense against a world full of potentially dangerous disease causing agents. It is a complicated beast that does a fantastic job of keeping us safe and well.

Recently, however, there was an interesting study suggesting that a genetic risk factor for Parkinson’s may be associated with an over-reaction from the immune system in response to infection from a common human food poisoning bug.

Specifically, mice who were missing the gene PINK1 literally had an ‘autoimmune reaction’ to the infection – that is the immune system began attacking healthy cells of the body – while normal mice (with intact PINK1 genes) recovered from the infection and went about their business.

In today’s post, we will explore this new research and discuss why we may need to rethink PINK.

 

Source: Huffington Post

I have had a guts full of all this gut research being published about Parkinson’s.

[NOTE 1.: For the unitiated: A “guts full” – Adjective, Kiwi colloquialism. Meaning ‘Had enough of’, ‘fed up of’, ‘endured to the point of tolerance’]

[NOTE 2.: The author of this blog is a Kiwi]

I really can’t stomach anymore of it.

And my gut feeling suggests that there is only more to come. It would be nice though, to have something else… something different to digest.

So what is today’s post all about?

Gut research of course.

But this gut research has a REALLY interesting twist.

Continue reading “A re-think of PINK” →

Time to resTOR in New Zealand

~ Simon ~ 15 Comments

 

As the amazing Australian Parkinson’s Mission project prepares to kick off, across the creek in my home land of New Zealand, another very interesting clinical trial programme for Parkinson’s is also getting started. The study is being conductetd by a US biotech firm called resTORbio Inc.

The drug being tested in the study is called RTB101.

It is an orally-administered TORC1 inhibitor, and it represents a new class of drug in the battle against Parkinson’s. 

In today’s post, we will look at what TORC1 is, how the drug works, the preclinical research supporting the trial, and what this new clinical trial will involve.

 

Rapa Nui. Source: Chile.Travel

Today’s post kicks off on an amazing south Pacific island… which is not New Zealand.

In 1965, a rather remarkable story began in one of the most remote inhabited places on Earth – the mysterious island of Rapa Nui (or “Easter Island”).

And when we say ‘remote’, we really do mean remote. Did you know, the nearest inhabited island to Rapa Nui is Pitcairn Island, which is 2,075 kilometres (1,289 mi) away. And Santiago (the capital of Chile) is 2,500 miles away – that’s a four-hour+ flight!!!

Rapa Nui is the very definition of remote. It is as remote as remote gets!

Does Amazon deliver to the town of Hanga Roa? Source: Atlasandboots

Anyways, in 1965 a group of researchers arrived at Rapa Nui with the goal of studying the local inhabitants. They wanted to investigate their heredity, environment, and the common diseases that affected them, before the Chilean government built a new airport which would open the island up to the outside world.

It was during this investigation, that one of the researchers – a University of Montreal microbiologist named Georges Nógrády – noticed something rather odd.

What?

At the time of the study, wild horses on Rapa Nui outnumbered humans (and stone statues).

Wild horses roaming the east coast of Rapa Nui. Source: Farflungtravels

But what was odd about that?

Georges discovered that locals had a very low frequency of tetanus – a bacterial infection of the feet often found in places with horses. He found this low incidence of tetanus particularly strange given that the locals spent most of their time wandering around the island barefoot. So Georges decided to divide the island into 67 regions and he took a soil sample from each for analysis.

In all of the vials collected, Nógrády found tetanus spores in just one vial.

Something in the soil on Rapa Nui was extremely anti-fungal.

In 1969, Georges’ collection of soil samples was given to researchers from the pharmaceutical company Wyeth and they went looking for the source of the anti-fungal activity. After several years of hard work, the scientists found a soil bacteria called Streptomyces hygroscopicus which secreted a compound that was named Rapamycin – after the name of the island – and they published this report in 1975:

Title: Rapamycin (AY-22, 989), a new antibiotic
Authors: Vézina C, Kudelski A, Sehgal SN.
Journal: J Antibiot (Tokyo). 1975 Oct;28(10):721-6.
PMID: 1102508              (This report is OPEN ACCESS if you would like to read it)

It is no understatement to say that this was a major moment in biomedical history. So much so that there is actually a plaque on the island commemorating the discovery of rapamycin:

Source: DiscoveryMag

Why was the discovery of ‘anti-fungal’ rapamycin so important?!?

Continue reading “Time to resTOR in New Zealand” →

Deep Mitochondrial stimulation?

~ Simon ~ 7 Comments

 

 

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.

 

The worst thing. Source: Greatist

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”.

Source: Taskcracker

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.

Source: Granger

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.

What is deep brain stimulation?

Continue reading “Deep Mitochondrial stimulation?” →

Exercise: Taking the STING out of Parkinson’s

~ Simon ~ 11 Comments

 

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.

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One of my personal life goals. Source: Jobcrusher

Few experts would disagree that the benefits of exercise are many.

Adults who achieve at least 2.5 hours of physical activity per week have:

  • up to a 35% lower risk of coronary heart disease and stroke
  • up to a 50% lower risk of type 2 diabetes
  • up to a 50% lower risk of colon cancer
  • up to a 20% lower risk of breast cancer
  • a 30% lower risk of early death
  • up to an 83% lower risk of osteoarthritis
  • up to a 68% lower risk of hip fracture
  • a 30% lower risk of falls (among older adults)
  • up to a 30% lower risk of depression
  • up to a 30% lower risk of dementia

(Source: NHS)

But what about people with PD? What do we know about exercise and Parkinson’s?

Continue reading “Exercise: Taking the STING out of Parkinson’s” →