Parkinson's Disease Tulip


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Old 06-27-2017, 12:32 PM #1
Tupelo3 Tupelo3 is offline
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Default Tying together A-Syn, the gut and autoimmune response

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
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Old 06-28-2017, 07:01 AM #2
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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.

Last edited by jeffreyn; 06-28-2017 at 07:30 AM.
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Old 06-29-2017, 02:21 AM #3
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Default Theory of PD

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.
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Old 06-29-2017, 04:20 AM #4
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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).
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Old 06-29-2017, 02:27 PM #5
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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?
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Old 06-29-2017, 05:06 PM #6
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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.
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Old 06-29-2017, 07:25 PM #7
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Blackfeather asks a good question, one that should be asked for every piece of research: What should my response be?

I will reconsider again low dose aspirin. I took this for about the first 3 years after diagnosis, but I stopped taking it, mainly out of laziness.

"Recent epidemiological studies have revealed that therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing PD. Here, we examined the effects of NSAIDs ... on the formation and destabilization of alphaS fibrils (falphaS) at pH 7.5 and 37 degrees C in vitro, ... All examined NSAIDs, except for naproxen and indomethacin, inhibited the formation of falphaS in a dose-dependent manner. Moreover, these molecules dose-dependently destabilized preformed falphaS."

Reference:

[1] "Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro."
Hirohata M1, Ono K, Morinaga A, Yamada M.
Neuropharmacology 2008
Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. - PubMed - NCBI
Abstract only

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Old 06-30-2017, 10:16 AM #8
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Default Curcumin, Trazodone

In reply to Blackfeather. Yes, time is running out for many of us and to think that there is going to be a "cure" this year or next is, perhaps, wishfull thinking. One of the few molecules out there that could help fight PD is, I believe, curcumin and a lot of it. Also Trazodone at a higher dose.

Curcumin Treatment Improves Motor Behavior in α-Synuclein Transgenic Mice

Despite the low plasma levels and extensive metabolism of curcumin, these results show that dietary curcumin intervention correlates with significant behavioral and molecular changes in a genetic synucleinopathy mouse model that mimics human disease.

Also, a recent study on Trazodone. Get your doc to Rx it, need 100 mg at least. At the very least it will help you sleep.

https://www.psychologytoday.com/blog...in-wonder-drug

Scientists discover two repurposed drugs that arrest neurodegeneration in mice | University of Cambridge

Two older drugs could be 'repurposed' to fight dementia - National Library of Medicine - PubMed Health
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Old 07-03-2017, 07:49 AM #9
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Default Alpha-synuclein mobilies inflammatory response to pathogens ...

In relation to Tupelo3's initial post,

from the research paper [1]:
"... alpha-syn is expressed during a GI infection and mobilizes an inflammatory response ..."

or, in the wording of the press release [2]:
"The nervous system within the wall of the GI tract detects the presence of a pathogen and responds by releasing alpha-syn. Alpha-syn then attracts white blood cells to the site where it has been released."

This raises an obvious question: What triggers the de-mobilization of the inflammatory response?

It seems to me that if the presence of alpha-syn mobilizes an inflammatory response, then the obvious trigger for de-mobilization would be the clearing of alpha-syn. If this is correct, this would seem to explain the long-term presence of neuroinflammation in PwPs. A lot of un-cleared alpha-syn is known to be present in the neurons of the substantia nigra (and other areas) in PwPs.

Why isn't the alpha-syn being cleared? Here are 3 possibilities (of course there are many more):
(1) A mutation in the SNCA gene causes alpha-syn to be modified in such a way that it cannot be cleared by the usual mechanisms. Kiwi33 has shown that this might be true in only a small number of cases (post #4).
(2) One or more viral/bacterial/fungal infections (perhaps a particular combination of them) somehow cause alpha-syn to be modified in such a way etc. etc.
(3) A mutation in one of the genes which control the protein-clearing mechanisms (ubiquitin/proteasome or lysosome/autophagy systems).

As I said in an earlier post, I think they are getting close now. Hopefully it will not be very long before we see a major breakthrough in the search for the primary cause of sporadic PD.

[1] Research paper: "A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity", Stolzenberg et al., Journal of Innate Immunity, June 27 2017.
[2] Press release from Georgetown University: "Protein Associated with Parkinson’s Disease Linked to Human Upper GI Tract Infections", June 27 2017.
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Old 07-03-2017, 10:06 PM #10
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Default Speaking of genetic mutations ...

When I was preparing the previous post, I realized that I needed to deepen my understanding of genetics, genetic mutations, post-translational modifications etc. etc. As l was wondering where to start, I noticed a new post on "The Science of Parkinson's Disease" blog, which just by chance happens to focus on an aspect of genetics.

The omnigenics of Parkinson’s disease? | The Science of Parkinson's disease

And one of the links contained within that post just happens to lead to a "backgrounder" page titled "Genetics of PD".

Genetics of PD | The Science of Parkinson's disease

So I have my starting point.

Maybe others will also find these links to be of interest.
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