The danger of alpha synuclein treatments


Honestly, when I read this article I just couldn't believe this is what modern day researches are working on. In order to avoid the clumping they are making meds to just remove all forms of alpha-synuclein ? With all my respect, but I have serious questions about the intellectual capacity of people doing medical research. Even reading the article I wonder if the people interpreting this data have sufficient intellectual capacity.

I mean, alpha synuclein is in the brain for a reason. If it wasn't useful, it wouldn't have been there. Nobody is interested in decreasing the amount of alpha synuclein in the brain. There is only 1 interest ... remove clumped alpha synuclein. This can be done by removing clumped alpha-synuclein or declumping the clumped alpha-synuclein. Because scientific results showed that the clumped alpha-synuclein does cause damage to neurons and spreads from neuron to neuron. So I don't understand why the role of alpha-synuclein in PD is considered such a big mystery, as the article seems to claim.

Also all these other preclinical tests like MANF or stem cell therapy on animals with MPTP induced PD means just nothing. There is already enough evidence that these experiments mean nothing. The only useful experiments are on animals carrying a modified PD gene, and/or alpha-synuclein PD animal models. So for my the real mystery is why companies are still getting green light for clinical testing when their preclinical tests have not yet shown efficiency on more advanced PD animal models.

My conclusion is simple. The current clinical PD research climate is dissapointing. It doesn't look like finding the cure is top priority. Finding a med to make profit is top priority number 1.

i have to say mr x, i have pondered the same points, unfortunately i dont have the knowledge to answer them - perhaps Research can shed some light?

Hello Turnip and MisterX

These are excellent questions, and ones that I don't think we can answer yet in a satisfactory way I'm afraid!

You're absolutely right that removing the alpha-synuclein entirely won't be the solution to Parkinson's, clearly it's an important protein that nerve cells need to do their jobs properly. So treatments that halt alpha-synuclein production entirely are too simplistic.

The major problem is that we don't know enough about alpha-synuclein yet - and these are some of the big questions:

- what does the protein do inside nerve cells?
- how much do nerve cells need to be healthy and work normally?
- is alpha-synuclein involved in the spread of Parkinson's through the brain?
- are clumps of tangled alpha-synuclein (and Lewy bodies) damaging to nerve cells - or are they actually a red herring?

We have some clues to the answers to these but I don't think we've cracked any of them yet - and much of the evidence is conflicting. For instance, we know that in some rare inherited forms of Parkinson's people produce too much alpha-synuclein and we think this might cause their nerve cells to die. This new finding suggests the opposite may also be true, that mutations that mean too little alpha-synuclein is produced may also be damaging.

Nerve cells are very sensitive to the smallest imbalances - so too much or too little of any protein may be enough to trigger problems. Our challenge is to find out what type, and how much alpha-synuclein is 'just right', and try to find ways to achieve that in people with Parkinson's.

Best wishes


Research team

Dear Claire,

Thanks for your reply. But you just state the same as the research community I was criticizing. I think people in PD research are just making things too difficult and are not practical enough.

Let me quote what you said:

"We have some clues to the answers to these but I don't think we've cracked any of them yet - and much of the evidence is conflicting. For instance, we know that in some rare inherited forms of Parkinson's people produce too much alpha-synuclein and we think this might cause their nerve cells to die. This new finding suggests the opposite may also be true, that mutations that mean too little alpha-synuclein is produced may also be damaging. "

This is what I mean with being unpractical. Too much can be damaging, too little can be damaging. Nice to know but the answer to this question has almost no practical purpose. Because various recent articles have already shown that clumped alpha-synuclein kills neurons and spreads from neuron to neuron in the same way as the damaging protein in mad-cow disease. My reasoning is that these clumps should be the focus, not the normal alpha-synuclein. So why bother about the 'perfect' balance ?

Now, I do realize that science needs more and more evidence in order to state that clumped alpha-synuclein is the real culprit causing the biggest damage. But you know what really bothers me ? Science has a billion time more proof that MPTP induced PD animal models are definitely NOT a correct presentation of PD; or PD would have been cure already. Why does science neglect this fact ?

And before you say science knows this and isn't neglecting it, can you please explain me why in PD preclinical testing MPTP toxic models are chosen as THE standard PD models and why alpha-synuclein models aren't ? Given all the proof that science has that MPTP PD models are far from a real representation of PD, why are these models still considered the standard ? Why is MPTP PD model chosen above a-synuclein model ? There is more evidence that shows the a-synuclein model is a better representation than MPTP model. For example, neurotrophic factors seem to work on MPTP models, but not on a-synuclein model. And I am sure that I can find more meds that failed in clinical trials, but succeeded in MPTP models; and that would also fail in the a-synuclein model.

This starts to look like the beta amyloid hypotesis in AD research. The only thing researchers are talking about for decades is beta amyloid removal. And even though tons of trials have already shown that beta amyloid removal has no clinical benefit, there is still an unbelievable struggle in AD research community to let go of the abeta theory. Even though companies like tau therapeutics that proved their tau therapy slows down AD with 80-90 %, the community still speaks more about abeta than tau.

Oh, before I forget 1 thing ... let's see what the ceregene results are. They will be published soon. Ceregene is a neurotrophic factor. According to previous studies in an alpha-synuclein environment neurotrophic factors are not supposed to work.

Science is aware of this:

So I still get shocked everytime people speak about promising results they got from MPTP animal models.

Poor people:

Hi again Mister X

I think many researchers would agree with you that trying to reduce the production of the alpha-synuclein protein inside nerve cells is barking up the wrong tree and won't lead to effective treatments for Parkinson's.

There is a lot of debate and conflicting views in other areas of Parkinson's research too. For instance, some people are very excited by the prospect of stem cell therapies - while others think they are wasting their time. I find it amazing actually because whenever I hear a scientist speak I hear a different perspective on Parkinson's and what the future might hold.

I guess it might sound a bit disheartening that Parkinson's researchers can't agree on a best way forward but actually I think it's one of the greatest strengths of the field at the moment. Researchers all over the world are working to solve the same problem but looking at it from so many different angles and challenging each other's findings at every stage.

The truth is in science we can never be sure who's on the right track and who's heading down a blind alley. But I think it's encouraging that there are so many different ideas being pursued (even though some of them will undoubtedly fail!).

One thing we can all agree on though is that current animal models of Parkinson's are not good enough. They don't reflect the slow, progressive loss of nerve cells inside the brain and they can't predict accurately whether a new treatment is going to be beneficial to people with Parkinson's. Genetic models of Parkinson's are being developed but there's no perfect model yet.

That's why developing better animal models is a key part of our research strategy;

Hope you had a lovely weekend.

Best wishes


Hi Claire,

Thanks again for your reply. I do agree that looking at it from different angles is the way to go. But I really hope they will not make the same mistake as the AD community where stuberness of the researchers caused the AD community to not pay sufficient attention to the importance of tau in AD.

I am happy to hear researchers are working to obtain better models. I think this is really KEY in PD research. Too much money is being wasted because the animal models do very badly represent human PD. I read about new animal models that carry the same faulty genes as people with PD. I think that's a very promising. I know people are working on this and already obtained interesting results with it.

And I think this is the right way to go. There are many genes known already that increase the odds of getting PD. Preclinical and clinical trials could easily take this into account. Take the example of Amicus Therapeutics. They focus on the GBA gene that increases the odds of getting PD. They tested it on a strain of mice with wrong GBA gene and are now very close to start clinical trials with their product. This is the professionalism I would expect from the scientific community. Not just keep testing all their stuff on a model that has proven for decades that it is by far a good representation of PD in humans. This was the only possible strategy 10 years ago. But now much more is known about PD and therefore PD community has to evolve based on that knowledge.

And also all these clinical trials where all people with different faulty genes are just mixed together. For me, this is in many cases a waste of time and money. And a recent research article also showed that this is not the way to go. Rapamycin was testen on neurons with different faulty genes. For a first type of faulty genes Rapamycin showed to be neuroprotective, for other type of faulty genes not. So mixing people together in clinical trials just isn't the way to go.

So actually my complaint is that the PD community seems to lack flexibility and doesn't adapt as fast as I expected. I really hope something happens with this respect.

A nice weekend for you too, Claire.