Tagged: Parkin

When miro just can’t let go

 

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?

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A re-think of PINK

 

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.

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Time to resTOR in New Zealand

 

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?!?

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Deep Mitochondrial stimulation?

 

 

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?

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Exercise: Taking the STING out of 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.

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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?

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Lipid issues in ER = ZZZ issues in PD

New research provides some interesting insight into particular cellular functions – and possibly sleep issues – associated with Parkinson’s.

Researchers in Belgium have recently published interesting findings that a genetic model of Parkinson’s exhibits sleep issues, which are not caused by neurodegeneration, but rather neuronal dysfunction. And as a result, they were able to treat it… in flies at least.

In today’s post, we will review this new research and consider its implications.


Source: Dlanham

I am a night owl.

One that is extremely reluctant to give up each day to sleep. There is always something else that can be done before going to bed. And I can often be found pottering around at 1 or 2am on a week night.

As a result of this foolish attitude, I am probably one of the many who live in a state of sleep deprivation.

I am a little bit nervous about doing the spoon test:

 

 

 

 

 

But I do understand that sleep is very important for our general level of health and well being. And as a researcher on the topic, I know that sleep complications can be a problem for people with Parkinson’s.

What sleep issues are there for people with Parkinson’s?

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Blessed are the suppressed

Recently a study was published in which the researchers had used a large dataset from the the United States Medicare system. The dataset held medical prescriptions for beneficiaries aged 60–90 years.

In their analysis, the researchers found that several diagnoses commonly treated with immunosuppressant medications were inversely associated with Parkinson’s – suggesting that perhaps the immunosuppressants may be reducing the risk of developing PD.

When they looked closer at the immunosuppressants, the investigators found that of the six categories of immunosuppressants, two were clearly associated with a lower risk of PD.

In today’s post, we will discuss what immunosuppression means, we will review the data, and  we will consider some of the issues associated with immunosuppressants.


George Hitchings and Gertrude Elion. Source: Achievement

After her grandfather died of stomach cancer and her fiance died of inflammation of the heart, Gertrude Elion dedicated herself to a future in medical research.

But despite a passionate love for laboratory research and having an excellent academic record, she was unable to get a graduate fellowship (or even an assistantship) due to the gender discrimination that existed at the time.

In the late 1930s, she enrolled in secretarial school with the goal of saving enough money to continue her education and achieve her goal.

After a year and a half of temporary secretarial and teaching positions, having saved up enough money, Elion enrolled as Master’s student in chemistry at New York University. She worked part-time as a receptionist and later as a substitute teacher to pay for her expenses. And she spent nights and weekends in the laboratory doing her research. She completed her degree in 1941.

George & Gertrude in action. Source: Wikimedia

In 1944, Gertrude was hired by George Hitchings who was working at what is now the pharmaceutical company GlaxsoSmithKline. It was the beginning of an amazing collaboration! And even though she never achieved a PhD, the work that she and Hitchings did together – research that won them the 1988 Nobel Prize in Physiology or Medicine – not only changed the way we design new drugs, but also gave the world its first drugs for immunosuppression.

What is immunosuppression?

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Two birds, one stone?

This week interesting research was published in the journal EMBO that looked at the Parkinson’s-associated protein Leucine-rich repeat kinase 2 (or LRRK2).

In their study, the researchers discovered that lowering levels of LRRK2 protein (in cells and animals) affected the ability of Mycobacterium tuberculosis – the bacteria that causes Tuberculosis – to replicate.

In today’s post, we will discuss what Tuberculosis is, how it relates to LRRK2 and Parkinson’s, and we will consider why this is potentially REALLY big news for Parkinson’s.


Daedalus and Icarus. Source: Skytamer

In Greek Mythology, there is the tale of Daedalus and Icarus.

Daedalus was a really smart guy, who designed the labyrinth on Crete, which housed the Minotaur (the ‘part man, part bull’ beast). For all his hard work, however, Daedalus was shut up in a tower and held captive by King Minos to stop the knowledge of his Labyrinth from spreading to the general public.

Source: Clansofhonor

But a mere tower was never going to stop Daedalus, and he set about fabricating wings for himself and his young son Icarus (who was also a captive).

Being stuck in the tower limited Daedalus’ access to feathers for making those wings, except of course for the large birds of prey that circled the tower awaiting the demise of Daedalus and his son. But he devised a clever way of throwing stones at the birds in such a way, that he is able to strike one bird and then the ricochet would hit a second bird.

And thus, the phase ‘killing two birds with one stone’ was born (or so it is said – there is also a Chinese origin for the phrase – Source).

Interesting. And this relates to Parkinson’s how?!?

Well, this week researchers in the UK have discovered that a protein associated with Parkinson’s is apparently also associated with another condition: Tuberculosis. And they also found that treatments being designed to target this protein in Parkinson’s, could also be used to fight Tuberculosis.

Two birds, one stone.

What is Tuberculosis?

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DUBstop: Oxford-style

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This week multiple research groups at the University of Oxford and Boston-based FORMA Therapeutics announced a collaboration to identify, validate and develop deubiquitinating enzyme (DUB) inhibitors for the treatment of neurodegenerative conditions, like Parkinson’s.

But what exactly are DUB inhibitors? And how do they work?

In today’s post, we will answer these questions, look at what the new collaboration involves, and look at what else is happening with DUB inhibitors for Parkinson’s.


dubstep_color_and_white_by_dtfproductions-d3admfb

Source: Blog4dubstep

Dubstep is a genre of electronic dance music that originated in South London in the late 1990s. Only recently -in the 2010s – has the culture really become more mainstream. And while I have a hard time appreciating the heavy bass music (man, I am becoming a grumpy old man before my time), it is amazing to watch some of the dancers who robotically embody this form of music:

The guy on the right is named Marquese Scott. Sometimes he simply defies the laws of physics.

The title of today’s post is a play on words, because rather than doing ‘Dubstep’ we are going to be discussing how to ‘DUB-stop’.

Researchers in Oxford have recently signed an agreement with a US company to focus resources and attention on a new approach for tackling neurodegenerative conditions, including Parkinson’s.

What they are proposing is a complicated biological dance.

Their idea: to stop deubiquitinating (DUB) enzymes.

What are deubiquitinating enzymes?

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UDCA 2.0 = TUDCA?

Ursodeoxycholic acid (UDCA) has been proposed as a drug that could be repurposed for Parkinson’s. As a medication, it is called ‘Ursodiol‘ and it is used to treat gallstones.

But there are absorption issues with UDCA: The passage of UDCA through the wall of the small intestine is slow and incomplete (Source).

There may be a solution, however, called Tauroursodeoxycholic acid (TUDCA). Think of it as UDCA-2.0. It is more easily absorbed by the gut. And there is also good evidence to suggest that it has the same beneficial neuroprotective properties as UDCA.

In today’s post we will discuss what exactly UDCA and TUDCA are, review the Parkinson’s research for both, and discuss why one of these drugs should be tested in the clinic for PD.


Gallstones – ouch! Source: Healthline

Let me introduce you to your gallbladder:

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. 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).

Source: Mayoclinic

Now, let me introduce you to your 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?

One of the treatments for gallstones is called UDCA. And this compound is being considered for “repurposing” as a treatment for Parkinson’s.

What is UDCA?

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