Parkinson disease and Mad Cows

Irish Cows

Irish Cows

MAD COW DISEASE! The very name conjures a sort of “pastoral interruptus” in which cows lazily grazing on a grassy knoll are overtaken by a seizure-like episode, one by one succumbing and tipping over, their legs stiffly extended skyward. Dire warnings follow, lest the Bovine Spongiform Encephalitis get into the human food chain and cause a variant of Creutzfeldt-Jakob disease (vCJD).

In the early 1980’s Dr. Prusiner of UCSF described a unique disease mechanism whereby a normal brain protein misfolds, and the protein itself serves as an infectious agent in the absence of known pathogens like bacteria and viruses. He coined it the “prion” protein, derived from the words “proteinacious” and “infectious.” These infective prions literally cascade from cell to cell within the brain, acting as a template to guide the misfolding of additional proteins, which clump and hijack the normal functioning of cells leaving characteristic sponge-like holes in its wake.

Just as with Parkinson and Alzheimer diseases, some of the group of prion diseases are caused by a specific genetic change in the offending protein. Shortly after Dr. Prusiner’s won the 1997 Nobel Prize in Physiology or Medicine for his ground-breaking work, I saw a family in which several members had one of the known genetic variants of the disease. I remember feeling something akin to revulsion as I pondered what it must feel like to know something is spreading inside you, something that is impervious to an army of anti-infectious soldiers as well as to sterilization—a phenomenon not unlike the spread of cancer, I thought.

Recently, a similar self-propagating mechanism has been described for Parkinson disease in which misfolded alpha-synuclein spreads from cell to cell inducing a characteristic protein clumping. Coined “permissive templating,” it helps explain the less than stellar results from the 1990’s when cell transplants were used to replace the dopamine-deficient cells in Parkinson disease—the transplanted tissue ultimately became “infected” which defeated the purpose of the intricate procedure.

Well, now, that’s a bummer! Diagnosed with a Mad-Cow-like disease of my own and awaiting my turn at keeling skyward, the cascade occurring inside my brain, is more than disturbing!

But wait—one can always make a loaf of banana bread from a bunch of rotting bananas! A recent publication reports taking advantage of the new-found, prion-like status of Parkinson’s with a view toward treatment of both diseases. A German research group has used high-throughput screening and found a compound which prohibits formation of the pathological forms of both prion protein and alpha-synuclein {Wagner J, Ryazanov S, et al, Acta Neuropathol (2013) 125:795-813}.

Will this likely be the “magic bullet?” Perhaps not, but it opens yet one more approach to the repertoire of treatment advances which has resulted from our description of that first Parkinson disease-causing mutation in alpha-synuclein.

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