Explanation for why PD progression might accelerate during bouts of fever/infection?
 

A research paper from June 2016 [1] describes how, during bouts of fever or infection, the mitochondria within the dopamine neurons of a PWP could (attempt to) signal the immune system to kill the neuron.

Basically, the mitochondria release a specific protein, which is transported to the wall of the cell, where it acts as an antigen, signalling T cells to attack the neuron.

This process is normally prevented from occurring by the actions of the proteins Parkin and PINK1 (except in the case of those PWPs whose Parkin and/or PINK1 genes are defective).

Neuron Cell Death in Parkinson's May Be Caused by Overactive Immune System

However, as reported in another research paper [2], in (all?) PWPs the c-Abl enzyme interferes with the normal operation of Parkin.

[1] Matheoud et al. (2016) Parkinson's Disease-Related Proteins PINK1 and Parkin Repress Mitochondrial Antigen Presentation, Cell 166, 314-327, doi: 10.1016/j.cell.2016.05.039.

[2] Brahmachari et al. (2016) Activation of tyrosine kinase c-Abl contributes to a-synuclein-induced neurodegeneration. J Clin Invest. doi: 10.1172/JCI85456.

Does anyone have personal experience of sensing that their PD has advanced noticeably after having a bout of fever or infection?

Also, can anyone point to where this topic has been discussed? I have a link which indicates that this is a topic of current research interest, but few details as yet.

slugmaniac comments on Scientists of Reddit, what's a phenomenon in your field that the average person hasn't heard of, that would blow their mind?

(I think the link came from a post/comment at HU)

Anti rejection drugs
 

Maybe someone will make a connection between this study and anti rejection drugs and get the FDA to approve a QUICK trial on PD patients..

Could Toning Down Calcineurin Neutralize α-Synuclein? | ALZFORUM

Webster's example of an "Oxymoron": FDA and Quick

Does anyone have personal experience of sensing that their PD has advanced noticeably after having a bout of fever or infection?
No, I've never had a fever, infection or even a mild cold since being diagnosed with PD.

Also, can anyone point to where this topic has been discussed?
The best review of this topic that I've come across is this one

Why is there motor deterioration in Parkinson’s disease during systemic infections-a hypothetical view
http://www.nature.com/articles/npjparkd201514

Also may want to check this one out:
Umemura A, Oeda T, Tomita S, Hayashi R, Kohsaka M, Park K et al. Delirium and high Fever are associated with subacute motor deterioration in Parkinson disease: a nested case-control study. PLoS One 2014; 9: e94944.

You've just described the theory of why c-Abl inhibitors (e.g. Nilotinib) may be neuroprotective.

During a search suggested by GerryW (on a different thread), I discovered where the second link (in my first post) probably came from!

https://www.neurotalk.org/parkinson-...s-quickly.html

Thanks curem (and GerryW).

Tupelo3 said: "You've just described the theory of why c-Abl inhibitors (e.g. Nilotinib) may be neuroprotective."

I would say "a theory" rather than "the theory". There are (at least) several theories.

From my second reference (Brahmachari et al.): "... we report a key and defining role for c-Abl activation in a-synuclein-induced neurodegeneration. In particular, our study implicates that selective inhibition of c-Abl could be neuroprotective."

Here is another one, this time involving the PARIS protein.

https://www.neurotalk.org/parkinson-...e-neurons.html

Jeffrey, my comment was really made tongue-in-cheek. However, if you want to be literal, I believe my comment is actually correct.

All of the research you mention is just support of the same basic theory. Essentially, the two kinases, Parkin and Pink1, add a protein called ubiquitin to PARIS, resulting in it's breakdown. PARIS is critical for proteasome-mediated protein clearance (particularly a-syn) and helps protect against the loss of dopamine neurons. The tyrosine kinase Abelson (c-Abl) is known to interact with many genes, and their protein products. Two of those, specifically, are Parkin and Pink1. c-ABL phosphorylates parkin, which inhibits its ligase activity, leads to substrate accumulation, and interferes with its protection against neurotoxicity. Recent analyses from PD patients and animal models of PD show an increase in the level of c-Abl, suggesting that the gene, and it's kinase, may be dysfunctional in PWP. This leads to the theory that reducing c-abl will reduce the breakdown of other kinases, like Parkin and Pink1, allowing them to function normally in protein clearance. The Brahmachari et al. study you noted demonstrated that deletion of the gene encoding c-Abl reduced α-synuclein aggregation and neurobehavioral deficits whereas overexpression of the constitutively active c-Abl accelerated α-synuclein aggregation, neuropathology, and neurobehavioral deficits. This study was a major component of the the research theory in the protocol for both the Georgetown and MJFF et al new trials.

I know this is an over-simplification, but this is the theory that backs all three of the upcoming trials. What other theories are there behind the use of a c-Abl inhibitor as a neuroprotective agent?

Tupelo3, thanks very much for your substantial response.

I used the word "theory" when perhaps I should have been using the word "hypothesis".

Hypothesis No 1:
During bouts of fever or infection, the mitochondria within dopamine neurons release a specific protein, which is transported to the wall of the cell, where it acts as an antigen, signalling T cells to attack the neuron. This process is normally prevented from occurring by the actions of the proteins Parkin and PINK1, except in PWPs, where the c-Abl enzyme interferes with the normal operation of Parkin.

​Hypothesis No 2:
From your text: "... the theory that reducing c-Abl will reduce the breakdown of other kinases, like Parkin and Pink1, allowing them to function normally in protein [e.g. alpha-synuclein] clearance."

Hypothesis No 3:
Within the dopamine neurons of non-PWPs, PINK1 proteins phosphorylate PARIS proteins, and this then enables Parkin proteins to ubiquitinate PARIS proteins, and this then enables PARIS proteins to be degraded by proteasomes. This keeps the number of PARIS proteins in check, thus ensuring that dopamine neurons are not killed by excess amounts of the PARIS protein. However, in PWPs, c-Abl interferes with Parkin, and this stops Parkin from being able to ubiquitinate PARIS.

All three hypotheses have in common the phosphorylation by c-Abl of Parkin. They all support a general "theory" (or broad hypothesis) that inhibition of c-Abl may be neuroprotective.

Respectfully, in all three of the hypotheses you present the inhibition of c-Abl are the exact same. What you're trying to postulate is what may cause malfunction in the first place. Maybe its environmental like fever, infection, or other toxin. Maybe it's genetic. Maybe it's some other cause we haven't even thought of yet. Nevertheless, in each of your hypotheses, there are no differences once you get to the point oh inhibiting c-Abl. I would be inclined to agree with you if there was evidence, or even a theory (or hypothesis) that c-Abl inhibition reacted differently with genetically mutated Parkin as opposed to environmentally malformed Parkin (associated with idiopathic PD). But, I am not aware of that, at this time.

I think you really are more focused on the theories of the root cause of PD. That goes way beyond any theory or hypothesis as to why c-abl inhibition may be neuroprotective for people with neurological diseases.