I apologize if someone has already posted this research, but I thought it was a superb study tying together A-syn, the gut and auto-immune response.

A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity - FullText - Journal of Innate Immunity - Karger Publishers

Protein Associated with Parkinson’s Disease Linked to Human Upper GI Tract Infections | Georgetown University Medical Center | Georgetown University

Thanks for posting this Tupelo3.

I'd like to make a couple of points regarding the research paper.

"the discovery reported here extends the hypothesis of Braak et al. that PD begins in the ENS by proposing that PD results from the excessive response of a normal innate immune component of the ENS"

I think they are almost there, but something is still missing. Otherwise every kid who got lots of viral infections of the GI tract would end up getting PD later in life.

"Since it is known from genetic studies that individuals with multiple copies of alpha-syn invariably develop PD, an increase in the expression of alpha-syn is sufficient to cause PD."

I think "invariably" is incorrect - I think the correct figure is less than 100% [1]. Also, there is a basic error of logic in this sentence. Even if 100% is the correct figure, an increase in the expression of alpha-syn is not necessarily sufficient to cause PD. It might also require the presence of, say, a second mutation, which has not yet been identified.

Back to my first point. Perhaps the "something" that is still missing is indeed a genetic mutation, which prevents alpha-syn from being cleared in the usual way.

I acknowledge that it seems unlikely that such a mutation, if it exists, would not have already been identified.


[1] Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease, Polymeropoulos et al., Science. 1997 Jun 27;276(5321):2045-7.

While waiting for Tup to get back from his trip, I've been doing a bit more thinking (always a dangerous thing!). Anyhow, here is the result.

Theory of PD
-----------------

To get PD, you must produce a lot of alpha-synuclein during your life, either by:
- having duplicates or triplicates of the SNCA gene (i.e. familial form of PD);
- having lots of viral/bacterial/fungal infections of the GI tract;
- growing old.

But not just normal alpha-synuclein. It must be alpha-synuclein which has one (or more) of the many possible mutations that cause it to mis-fold and aggregate, and prevent it from being cleared in the usual way.

Each mutation of alpha-synuclein only affects a small proportion of PwPs. But because there are many different mutations, they collectively affect a very large proportion of PwPs. [1]

[1] "... the common disease - common variant hypothesis, which states that genetic susceptibility to common diseases like hypertension, diabetes and PD are largely because of alleles that have moderate frequency in the population. ... While these known and yet unknown variants may individually contribute to a small proportion of disease susceptibility, collectively these variants could account for a significant fraction of disease risk." [A]

[A] Alpha-Synuclein and Familial Parkinson’s Disease, Pankratz et al., Mov Disord. 2009 June 15; 24(8): 1125–1131.

Thanks jeffreyn.

It seems that variations in the copy number of the SNCA gene (and other genes) can be risk factors for both familial and sporadic PD (Copy number variability in Parkinson’s disease: assembling the puzzle through a systems biology approach).

The evidence for point mutations in the SNCA gene is less clear. The way to do this is a Genome Wide Association Study (GWAS). In this context a GWAS means recruiting a lot of people with PD and compare them with matched people without a PD Dx.

The only GWAS that I can find suggests that SNCA mutations can be risk factors but these are rare, occurring in about 2% of people with sporadic PD (Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson’s Disease).

With all the latest data about PD beginning in the gut, the gut/brain axis and PD being an auto immune illness, how do we translate this information into some kind of treatment protocol. For those pwp for whom time is running out, who
want to take some measures to slow or reverse this disease, do we now have a more focused direction to go in using existing approved drugs or supplements? Would an old drug like cholestyramine clean up the gut and remove toxins that cause inflamation and an alpha synuclein immune response? Would probiotics be helpful? What about squalamine, if it were available? There are obviously some very smart folks on this forum, citizen scientist who may have some good ideas about the nature of this illness. Where do we go from here?

There is some evidence that squalene may help by reducing the toxicity of α-synuclein though so far this has come from tissue culture and worm models. This is discussed here A natural compound can block the formation of toxins associated with Parkinson’s Disease | University of Cambridge - it includes a link to a free-access version of the original paper.