HYPE

[Xenos]

Chasing alpha-synuclein...

medicalnewstoday.com/articl...

[jimcaster]

If only we knew for sure that alpha synuclein is the right target...

[Xenos in reply to jimcaster]

If only... You'r right.

[WinnieThePoo in reply to jimcaster]

There's a lot of stuff going on with A-syn. I think we'll have a good idea before too long

[Xenos in reply to WinnieThePoo]

The most recent papers leads one to think that Lewy bodies are just a reaction to another aggression on the neurons. Some sort of garbage collecting within the cell.

[WinnieThePoo in reply to Xenos]

Lewy bodies in post mortem exams defined PD, but A-syn misfolding has been investigated separately. Abnormal A-syn expression and misfolding are implicated in a number of studies recently. They're not the same thing.

[jimcaster in reply to WinnieThePoo]

Is it fair to say we are still unclear as to whether alpha synuclein clumps are a cause or an effect of PD?

[WinnieThePoo in reply to jimcaster]

I think it's fair to say we still don't know. But the recent research regarding misfolding A-syn migrating from the gut to the brain via the vagus nerve suggests cause

[WinnieThePoo in reply to WinnieThePoo]

Perhaps cause isn't strictly correct. Mechanism might be a better term. The cause would be whatever causes A-syn to over-express and misfold in people with PD. However from a therapeutic perspective what matters is whether the bad A-syn, once present, is contributing to the disease manifestation. And if it is, whether removing or controlling it contributes to improvement in that disease progression or manifestation. That is a possibility that I have yet to dismiss based on what I have understood to date.

[ElliotGreen in reply to jimcaster]

It's looking more and more like the clumping of alpha-synuclein can lead to neural cell death and thus PD.

nature.com/articles/s41467-...

[jimcaster in reply to ElliotGreen]

I know that's the conventional wisdom and I hope we are on the right track, but I worry about being on the same track as Alzheimer's researchers ten years ago aiming at beta amyloid. Are protein or plaque like build ups a cause or effect. I have no idea...just a worry.

[jimcaster in reply to jimcaster]

This is what I am referring to. alzheimers.net/2014-04-07/b...

[WinnieThePoo in reply to jimcaster]

Within a couple of years we will have more information from spark and pasadena.

[Gioc in reply to WinnieThePoo]

For when are they assumed that these drugs will be available on the market if everything goes well?

[WinnieThePoo in reply to Gioc]

Not sure. Both are phase 2 trials implying that a further phase 3 would be required, so maybe 5 years from the end of the phase 2.

However they may give important clues to the role of A-syn before they are licensed drugs.

I think it is possible to fast track authorisation for a new medication where it meets a need for a serious medical condition like PD where no other solution already exists.

The spark trial at 311 participants over 2 years is a big phase 2, and if results were clearly unambiguously statistically significant compared with placebo, maybe it could be fast tracked

Edit: spark is also double blind placebo controlled randomised international multi-center. It's a lot like a typical phase 3 trial

[Gioc in reply to WinnieThePoo]

We hope, personally I lose a bit interest when I see that it takes 5 / 7 years to availability, but I hope it is the solution.

[WinnieThePoo in reply to Gioc]

I think it is possible to deliver earlier. But not before the end of the phase 2 earliest. So july 2021. If it works. But if it works then PD will be much less of a problem for those diagnosed in the future. And, a little selfishly, for me too.

[Gioc in reply to WinnieThePoo]

Everyone in HU places their expectations and certainties in what they consider most appropriate for him in respect of the expectations of the other, until a cure will be available and there will be certainty for all.

I hope your solution is as effective as I hope it is for mine, we are still in the same boat.

[WinnieThePoo in reply to Gioc]

Agreed. Better to hope a solution will be found than to celebrate failure which helps none of us. A cure is not going to be found in natural remedies just because they are immediately available. (With the possible exception of the gut brain axis) . Exercise, supplements, B1 help ameliorate or complement therapies, but are not providing a solution which persuades me to hope scientific research will fail

[Xenos in reply to WinnieThePoo]

At the same time, I remember of Lorenzo's Oil. It was a true story...

[Gioc in reply to WinnieThePoo]

In fact, nobody wants to persuade you. If the human brain is considered the most complex object in the universe it is likely that we are living in prehistory and it is likely that many discoveries have yet to be made before we understand the mechanisms of brain cell life. There are many things we don't know. The more fundamental a discovery is the more it aligns and explains the data and complexity above it and the mitochondrial theory in my opinion aligns more data than the a-Syn theory, but I could be denied. IMHO we have to find out why dopaminergic cells suffer and die and the pwp mitochondria seem very bad.

I personally have an impulse to survive and not I will wait 5/10 years without doing anything to counteract neurodegeneration and for me it only counts the results: if it works it is true, medicine or supplement.

[Despe in reply to WinnieThePoo]

Winnie, I am not holding my breath.

[WinnieThePoo in reply to Despe]

You may be confusing PD with hiccups. 😉

I remain interested in this research

[aspergerian13]

Recently, a listmate posted a link to a 2016 study reporting that a virus within the cns induces alpha synuclein expression.

[aspergerian13 in reply to aspergerian13]

Google this:

alpha synuclein antimicrobial

[WinnieThePoo]

The "is it, isn't it" A-syn debate on this forum has got spread over a number of threads, so not sure where best to post. This is a recent (2019) paper of interest to me as a participant in spark

google.com/url?sa=t&source=...

[aspergerian13 in reply to WinnieThePoo]

Thanks for the link. The rationale presented in the abstract is very similar to the amyloid-beta rationale regarding Alzheimer's disease.

[sunvox]

I don't have time to put together all the papers right now, but I will simply say at this point that there is overwhelming evidence that "mis-folding" is a common issue in several diseases including Parkinson's. The scientific term is oligomerization. I am not a scientist, but the way my brain explains this is that the protein is a key that is looking for a keyhole. If it can not find a proper keyhole it ends up hanging around and causing damage then finally ends up in a clump. The clump is a byproduct of the process, but not the cause of damage. The question for Parkies is why does their protein become an oligomer, genetics, trauma, gut troubles? The answer appears to be varied. Also alpha-sy is all over the body so the problem is not localized.

[WinnieThePoo in reply to sunvox]

My understanding is that it is the mis-folded, abnormal A-syn which is the problem. It has been shown that it can be transmitted from cell to cell. It would be elegantto know why the protein misfolds, but not essential (recent research suggests it starts in the gut, so may be microbiome balance linked, probably with genetic factors).

Regular A-syn is an important protein for normal cell function.

The first issue for me as a PWP is , if bad A-syn is significantly influencing or causing some or most symptoms, as well as disease progress can it be removed? And if so, will the disease stop progressing, and the symptoms improve?

The SPARK and PASADENA trials may shed some light on this. I remain hopeful.