A new theory proposes that the accumulation of alpha-synuclein occurs simultaneously in nerves throughout the body, and that the various parts of the nervous system differ in how much toxicity they can tolerate.

Parkinson's Researchers Offer New Theory for Origin of Disease

It is interesting that, even in their latest paper, Braak and Del Tredici do not rule out such a possibility [1].

"Gradually, three questions emerged: (1) Does sporadic PD begin in the substantia nigra or elsewhere? (2) Do vulnerable regions in all divisions of the human nervous system become involved at the same time? (3) Does the distribution of Lewy pathology in susceptible nonnigral regions follow a recognizable pattern or sequence? These questions can be answered only when biomarkers of the underlying degenerative process, electrophysiological testing, and imaging modalities make it possible to assess and reassess one and the same individual at ongoing time points in life."

However, it seems to me that the Braak & Del Tredici paper also contains at least one piece of evidence supporting their Staging hypothesis against the new Threshold theory. This comes out of some research into surgeries done on the vagal nerve, which runs from the brainstem to the abdomen. Vagotomies were formerly performed to treat peptic ulcers. Full vagotomy involves resection of both vagal trunks. Selective vagotomy involves resection of only terminal branches of the vagal nerve that supply the fundus and corpus of the stomach.

"This [research] illustrates that the risk of having developed sporadic PD at followup more than ten years after surgical intervention was significantly reduced in individuals who had undergone full truncal vagotomy but remained nearly similar to the risk of the general population in persons with selective vagotomy."

The above article (1st link) also mentions vagotomy, but merely to say that if the "Threshold" theory is correct, vagotomies would become "unnecessary"!

[1] Neuropathological Staging of Brain Pathology in Sporadic Parkinson's disease: Separating the Wheat from the Chaff, Heiko Braak, Kelly Del Tredici, Journal of Parkinson's Disease 7 (2017) S73-87 DOI 10.3233/JPD-179001.

Neuropathological Staging of Brain Pathology in Sporadic Parkinson’s disease: Separating the Wheat from the Chaff - IOS Press

(this is an open-access document)

Thanks for those links jeffreyn - they are very interesting.

They remind me of a talk that I listened to at a conference a while ago. It was given by a guy from Cambridge with both a PhD and a medical doctorate.

He made the point that PD is not "one disease" in the same sense that cancer is not "one disease".

Rather, he argued that, although PD has some clinical signs in common, the underlying pathology may vary a lot between different people.

What I got from that is that "one size fits all" is not likely to be effective for different people with PD.

kiwi33 said: "They remind me of ..."

In my case the new theory reminded me of another PubMed Commons comment by Claudiu Bandea, in which he talks about (among other things) his own theory that alpha-synuclein is a member of the innate immune system, and that the assembly of alpha-synuclein into various oligomers and fibers is an integral part of its biological function in innate immunity.

Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. - PubMed - NCBI

Thanks for that jeffreyn - fascinating.

I think that I will spend some time this weekend pondering what Bandea has proposed.