Scientists uncover strong support for once-marginalized theory on Parkinson's disease

http://www.bionity.com/en/news/13765...s-disease.html

So misfolded a-synuclein is killing dopamine neurons. So targeting them seems to be a good way to slow down the disease. However ... I still have some doubts about the vaccine trial that started last week. It is supposed to target a-synuclein. 10 years ago something similar was done for Alzheimer. The antibodies managed to remove almost (> 80 %) all plaques. If this vaccine has a similar succes it will remove 80 % of all a-synuclein. But is it really OK to remove all a-synuclein ? As fas as I have read, healthy people also have a-synuclein. Researchers have no idea what is the function of a-synuclein. But if it is there, I think there must be a good reason for it. So removing all a-synuclein seems pretty dangerous to me. I would put my hope on meds reducing a-synuclein but not on vaccins removing them all.

[lurkingforacure]

Originally Posted by Diego24

http://www.bionity.com/en/news/13765...s-disease.html

So misfolded a-synuclein is killing dopamine neurons. So targeting them seems to be a good way to slow down the disease. However ... I still have some doubts about the vaccine trial that started last week. It is supposed to target a-synuclein. 10 years ago something similar was done for Alzheimer. The antibodies managed to remove almost (> 80 %) all plaques. If this vaccine has a similar succes it will remove 80 % of all a-synuclein. But is it really OK to remove all a-synuclein ? As fas as I have read, healthy people also have a-synuclein. Researchers have no idea what is the function of a-synuclein. But if it is there, I think there must be a good reason for it. So removing all a-synuclein seems pretty dangerous to me. I would put my hope on meds reducing a-synuclein but not on vaccins removing them all.

A-syn is in all of us, yes, and no, no one knows what it's function really is. Compound that with the fact that they have found a-syn clumps in the brains of people without PD symptoms, even at advanced age, and what does this mean? Additionally, I seem to remember some Alz. trial where the drug reduced the tau tangles and people got WORSE faster than controls. I have serious doubts about whether the clumps are bad-what if they are some type of protection mechanism?

Since we really don't know...seems like the first order of business would be to really determine what causes the clumps in the first place. Clearing clumps is all fine and good, assuming they are what is killing the neurons (and see above, that is not a given) but only more will occur unless we know why they form and how we can prevent their formation.

Originally Posted by lurkingforacure

Additionally, I seem to remember some Alz. trial where the drug reduced the tau tangles and people got WORSE faster than controls.

WORSE ??? I read all articles about this yesterday. People didn't get worse. Some people died because their immune system started to attack their brain. Most didn't die but the vaccine didn't work for them. Only 20 % got antobodies to remove the plaques. As far as I read, after 4.6 years these people scored significantly better on dementia tests than placebo controlled people. So disease progression was slowed down. But in the end, these people died very dement so it wasn't a cure. Also, their brain shrank much more than placebo. This is something scientist didn't understand.

Originally Posted by lurkingforacure

Clearing clumps is all fine and good, assuming they are what is killing the neurons (and see above, that is not a given) but only more will occur unless we know why they form and how we can prevent their formation.

Well, read my first post again. Advanced computer simulations have shown that misfolded a-synuclein does attack the dopamine neurons. So I don't think misfolded a-synuclein is protecting neurons. The results of these simulations actually show that targeting misfolded a-synuclein will slow down the degeneration of the dopamine neurons because neurons will get less attacked. That, I don't doubt about.

What worries me is the vaccine clearing the brain from all a-synuclein. As you say people don't know what it does. If you don't know what it does, than just leave it there. I read that people with some gene defect can produce a lot of a-synuclein which gives rise to these clumps. So my bet is that a med shouldnt remove all a-synuclein but the right amount to stop this clumping and remove some of the existing clumps.

By the way, today I read about some researches who claim they found some molecule or protein present in the brain (I think it was hp90 or something like this) that is very much present in people with PD and causes the clumping. They are now focusing in finding some meds to stop this protein to cause the clumping. But of course, this is not for tomorrow.

I think, given the results of these computer simulations the current hope for PD slow down is removing a-synuclein combined with neurotrophic factors (cogane, ceregene, ...) and lots of sports and healthy food. At least after 4 weeks of intensive search and reading, this is my conclusion.

[jerzy]

You may be interested in protein vps41.
Some reading here: *edit*
Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human ortholog of yeast Vps41 protein which is also conserved in Drosophila, tomato, and Arabidopsis.
Can we remove a-synuclein by eating lots of tomatos?

[Conductor71]

This is quite interesting. I think the key here is that scientists once thought it was the fibril that was toxic; that is the end product of the alpha-syn and dopa neuron tango. LFAC is actually on the mark. There has never been clinical correlation between disease severity and the number of fibrils in the autopsied brain. This is because fibrils (as research now sees it) may actually represent recovered neurons.

Research over the past few years has shown it is more likely the middle stage oligomer formation of the protein that results in protofibrils. ( I am thinking this is the ring like structure in your article) ; this is where things get ugly. Thus, for any sort of alpha-syn inhibitor to be efficacious, it must know when to act or we have to be marked as probable for PD before onset of motor symptoms for the treatment to prevent or reverse things.

So it is not that we want to reduce Alpha-syn so much as we want to avoid misfolding which turns it toxic and discover why our dopamine neurons in just one relatively small part of the brain are so vulnerable. BTW, PD is looking more and more like a prion disorder much like our four legged friends get Mad Cow (noted for pore like toxic spread -turns brain into a sponge as it tunnels around). I'd like to see what we might learn from those prion forms; notably origin- it is suggested that a micro virus sets it off. Also makes you wonder if PD is somehow transmissible?

Incidentally, two common substances we have ready access to are showing promise in inhibiting or even halting alpha-syn oligomerization. The first is already present in us as Serotonin. The other many of us take in the form of Comtan. Yes, Entacapone may be neuroprotective. No studies have been done which is quite remarkable given the push on Azilect.

Laura

Here are a few links:

Amyloid Pores form Pathogenic Mutations.

Amyloid Fibrils of Mammalian Prion Protein Are Highly Toxic
to Cultured Cells and Primary Neuron.

The neurotransmitter serotonin interrupts α-synuclein amyloid maturation.

Entacapone and Tolcapone, Two Catechol O-Methyltransferase Inhibitors, Block Fibril Formation of α-Synuclein and β-Amyloid and Protect against Amyloid-induced Toxicity*

Originally Posted by Conductor71

So it is not that we want to reduce Alpha-syn so much as we want to avoid misfolding which turns it toxic and discover why our dopamine neurons in just one relatively small part of the brain are so vulnerable.

Interesting post, Laura. I have 1 remark though. You say we don't want to reduce a-synuclein, only the toxic one. I do agree but I also disagree with that. I read several times that some gene defects cause an overproduction of a-synuclein which in turn gives raise to the toxic a-synuclein aggregation. So I guess people with PD have too much a-sunclein so in order to stop the aggregation this MAYBE has to be regulated to lower levels.

Originally Posted by Conductor71

Entacapone may be neuroprotective.

However ... http://www.michaeljfox.org/living_vi...icle.cfm?ID=20

[Conductor71]

Originally Posted by Diego24

Interesting post, Laura. I have 1 remark though. You say we don't want to reduce a-synuclein, only the toxic one. I do agree but I also disagree with that. I read several times that some gene defects cause an overproduction of a-synuclein which in turn gives raise to the toxic a-synuclein aggregation. So I guess people with PD have too much a-sunclein so in order to stop the aggregation this MAYBE has to be regulated to lower levels.

Hi Diego,

I thank you for your thoughtful posts on research. I am by no means an expert, but I have exhaustively mined a lot of the literature over the last three years just for peace of mind; I haven't yet achieved it I am not sure where, if anywhere, this gets me; it's silly, but in being informed I feel that I am fighting back a little. I just cannot walk away with such a messy clinical picture and accept everything we are told at face value.

I suggested that interference with the protein misfolding stages because you and LFAC pointed out - alpha syn and the fibrils might be something more benign. More importantly, brains show that the amount of fibrils (essentially these originate with alpha-syn.) does not measure disease severity, so in my mind, it is the pathogenic loss of function in the protein that needs to be addressed. We could have normal levels of a-syn and still have PD; it only becomes toxic when it forms a ring structure - these rings accelerate in number and that is what wreaks havoc on our cells.

Current research seems to indicate that alpha-syn is essential to smooth to synaptic exchange between neurons, when these proteins misbehave they die off too (where else do they go?) Without having any clue about what is a "normal" level where is the tipping point to excess and how much do we reduce? We could end up harming ourselves in reducing the protein levels.

I think you refer to the SNCA mutation; they do have more than enough a-syn to spare. However, at the other end of the spectrum there is a Parkin mutation that does not result in Lewy Body fibrils. I think this just serves to highlight how there are many different paths to this same place; the only thing we may all here have in common symptom cluster - to me, an actual disease means we have one common way there. So for researchers to extrapolate from one genetic subset that has too much a-syn to Parkin subsets to the rest of us "sporadic" PWPs - well that is a stretch at best, imho.

It seems to me that manipulating the metabolic dysfunction is more doable and is potentially beneficial to more cases of PD than determining a-syn levels which are all over the place as indicated by genetic factors.

[reverett123]

1. Mol Nutr Food Res. 2006 Feb;50(2):229-34.

Green tea catechins as brain-permeable, natural iron chelators-antioxidants for
the treatment of neurodegenerative disorders.

Mandel S, Amit T, Reznichenko L, Weinreb O, Youdim MB.

Eve Topf, Haifa, Israel. mandel@tx.technion.ac.il

Neurodegeneration in Parkinson's, Alzheimer's, or other neurodegenerative
diseases appears to be multifactorial, where a complex set of toxic reactions,
including oxidative stress (OS), inflammation, reduced expression of trophic
factors, and accumulation of protein aggregates, lead to the demise of neurons.
One of the prominent pathological features is the abnormal accumulation of iron
on top of the dying neurons and in the surrounding microglia. The capacity of
free iron to enhance and promote the generation of toxic reactive oxygen radicals
has been discussed numerous times. The observations that iron induces aggregation
of inert alpha-synuclein and beta-amyloid peptides to toxic aggregates have
reinforced the critical role of iron in OS-induced pathogenesis of
neurodegeneration, supporting the notion that a combination of iron chelation and
antioxidant therapy may be one significant approach for neuroprotection. Tea
flavonoids (catechins) have been reported to possess divalent metal chelating,
antioxidant, and anti-inflammatory activities, to penetrate the brain barrier and
to protect neuronal death in a wide array of cellular and animal models of
neurological diseases. This review aims to shed light on the multipharmacological
neuroprotective activities of green tea catechins with special emphasis on their
brain-permeable, nontoxic, transitional metal (iron and
copper)-chelatable/radical scavenger properties.

PMID: 16470637 [PubMed - indexed for MEDLINE]

Originally Posted by Conductor71

Hi Diego,
I think you refer to the SNCA mutation; they do have more than enough a-syn to spare.

I brought this up because of my concern with the parkinson vaccines. 10 years ago they tested an Alzheimer vaccine and in some patients it remoced up to 80 % of the plaques. I think if the parkinson vaccin removes 80 % of a-synuclein people could get into troubles.

Originally Posted by Conductor71

However, at the other end of the spectrum there is a Parkin mutation that does not result in Lewy Body fibrils.

Are you sure about this statement ? I am reading about parkinson for 3 to 4 weeks only. But I don't remember Parkin mutation doesn't give raise to Lewy Bodies. I thought these Lewi Bodies were present in all form of Parkinson.

Originally Posted by Conductor71

I think this just serves to highlight how there are many different paths to this same place; the only thing we may all here have in common symptom cluster - to me, an actual disease means we have one common way there.

This is a good point. That is why I think the clinical trials are performed incorrectly. To give an example ... I read about a recent discovery in wich they found a gene that can predict whether your PD will progress very slow, slow, fast or very fast. So how can you do a clinical trial without taking this into account ?

Just take the following example. Lets say we do a phase 2 trial with 300 people. If you are unlucky maybe 100 of them progress very fas. If you are even more unlucky 80 of them will end up in the treatment group. So even if you test a product for it neuroprotectiveness and it DOES work, statistically you will still conclude that it doesn't work. Researcher can't just ignore the fact that some people progress faster than others, unless there would be biomarkers they could individually study and see each patients individual progress.

As you say, it is very possible that there are several forms of PD that probably will have to be cured differently. But at the basis, I do think all forms of PD have a common reason... there are toxins in their brain and the brains garbage collector isn't properly working. So solving 1 of the PD's will be beneficial for all other forms of PD. I think, at this stage, scientist would be thrilled if they could just solve 1 of the existing PD's.