Prion Protein Functions in Maintenance of Peripheral Myelin

The neuronal expression and regulated proteolysis of the normal, cellular prion protein (PrPc) are essential for the maintenance of peripheral myelin, according to an international team of researchers from institutions including Cal Tech and the University Hospital of Zurich. The integrity of peripheral nerves depends on communication between axons and the Schwann cells that produce myelin. Myelin insulates peripheral nerve axons and speeds electrical transmission. The axon signals that ensure myelin maintenance are distinct from those that direct myelination and are largely unknown, the authors wrote. The normal function of PrPc--that when misfolded into the scarpie-associated form (PrPsc) causes various transmissible fatal neurodegenerative diseases, including scrapie in sheep, mad cow disease in cattle, and Creutzfeldt-Jakob disease in humans--is also unknown. The current results appear to represent progress toward solving, at least in part, both of these puzzles. The authors showed that ablation of PrPc triggers a chronic demyelinating polyneuropathy (CDP) in four independently targeted mouse strains. CDP was triggered by depletion of PrPc specifically in neurons, but not in Schwann cells, and was suppressed by PrPc expression restricted to neurons but not to Schwann cells. CDP was prevented by PrPc variants that undergo proteolytic amino-proximal cleavage, but not by variants that are nonpermissive for cleavage, including secreted PrPc lacking its glycolipid membrane anchor. This work was published in the March issue of Nature Neuroscience. The seminal research identifying and characterizing prion proteins was recognized by the awarding of the Nobel Prize in Physiology or Medicine to Dr. Stanley Prusiner in 1997.
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