Undiscovered cause of Parkinson’s found for first time by scientists in huge breakthrough

[Sly Saint]

Scientists have made a potentially “life-changing” discovery that could pave the way for new drugs to treat Parkinson’s disease.

Experts have known for several decades that the PINK1 protein is directly linked to Parkinson’s disease – the fastest growing neurodegenerative condition in the world.

Until now, no one has seen what human PINK1 looks like, how PINK1 attaches to the surface of damaged mitochondria inside of cells, or how it is activated.

But scientists have now discovered how the mutation switches on and can start using this knowledge to find a way to switch it off and slow the progression of the condition down.

Researchers at the Walter and Eliza Hall Institute, Parkinson’s Disease Research Centre, in Australia, have solved the decades-long mystery.

The findings published in the journal Science reveal for the first time ever the structure of PINK1 and how it binds to mitochondria – the powerhouse of a cell – and stops it functioning properly.

Undiscovered cause of Parkinson’s found for first time by scientists in huge breakthrough

 

[Sasha]

Wow. I hope this could be us, one day.

 

[Utsikt]

Study, but only abstract (line-breaks added)
https://pubmed.ncbi.nlm.nih.gov/40080546/

Mutations in the ubiquitin kinase PINK1 cause early onset Parkinson's Disease, but how PINK1 is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood.

We determined a 3.1-Å resolution cryo-electron microscopy structure of dimeric human PINK1 stabilized at an endogenous array of mitochondrial TOM and VDAC complexes. Symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, both of which also bind PINK1 kinase C-lobes. PINK1 enters mitochondria through the proximal TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22.

Our structure explains how human PINK1 is stabilized at the TOM complex and regulated by oxidation, uncovers a previously unknown TOM-VDAC assembly, and reveals how a physiological substrate traverses TOM40 during translocation.

Post about it by the institution:
https://www.wehi.edu.au/news/scientists-solve-decades-long-parkinsons-mystery/

 

[Creekside]

"Fastest growing condition" sounds worrisome, but changing demographics (aging population) will lead to changes in rates of disease. So will changes in technology (effective tests for a disease), or changes in terminology (FND diagnoses rose rapidly after the term was coined).

I suppose ME or PEM could involve a similar abnormal protein that no one is aware of and won't be found until the right technology is developed, and someone looks in the right place under the right conditions.

 

[Jonathan Edwards]

I suspect this is another little piece of the jigsaw rather than a huge breakthrough. Unfortunately the press report makes no real sense so one doesn't know. I don't have time to read the full paper.

 

[Utsikt]

"Fastest growing condition" sounds worrisome,

There are probably many different ways to calculate ‘fastest growing’.

 

[Jonathan Edwards]

I suppose ME or PEM could involve a similar abnormal protein that no one is aware of and won't be found until the right technology is developed, and someone looks in the right place under the right conditions.

I think that is unlikely because conditions like Parkinson's and Alzheimer's are irreversibly progressive in a way that ME/CFS does not appear to be. People with ME/CFS may progress and worsen enough to need feeding support but some of them will then improve, as we seen pictures of.

There may well be rogue proteins derived from mutations involved in ME/CFS but I suspect they will be members of a 'normal' protein spectrum that happen to get caught up in immune control mechanisms. Antibodies would be an example but no the only possibility.

 

[Creekside]

I think that is unlikely because conditions like Parkinson's and Alzheimer's are irreversibly progressive in a way that ME/CFS does not appear to be.

Those are examples in which the abnormal proteins persist and/or accumulate. Couldn't there be diseases where the abnormal protein is transient? Maybe it last for only milliseconds, but that's long enough to interfere with some cellular function. I'm not pushing the idea, just pointing out that there's a lot we don't know, so lots of places ME's core dysfunction could be hiding.

 

[Jonathan Edwards]

Those are examples in which the abnormal proteins persist and/or accumulate.

I think in this example of early-onset Parkinson's the suggestion is that there is a mutation in a gene carried by every cell throughout life that foursome reason leads to damage specifically to certain brain cellist early adult life. I am not sure that the abnormal protein 'persists' or accumulates more than the normal one. In Alzheimer's what accumulate are 'tangles' of probably normal fibrillary proteins and also amyloid proteins. In prion disease abnormal proteins accumulate by inducing quaternary changes in each other's structure.

If a protein is abnormal because of a gene mutation it is abnormal for as long as it exists. If it is abnormal transiently after being made - i.e. because of post-translational modification - the changed molecules are unlikely to take on some consistent pathological function, just get scavenged. It might lead to some systematic pathological process perhaps but then the question would be what is causing the abnormal post-translational modification? And once initiated why would it stop doing so rather than lead to a progressive problem?

For antibodies we know that the story can allow for resolution because clones making each new antibody may come and go over periods of months or years.

There are certainly lots of unexplored possibilities but I am not sure that this particular form of Parkinson's disease is likely to be a a useful analogy.