Prion and TNF(alpha): TAC(E)it agreement between the prion protein and cell signaling.

Prion diseases are rare and fatal neurodegenerative disorders that occur when the cellular prion protein (PrP(C)) is converted into a conformationally modified isoform that originates the novel infectious agent, called prion. Although much information is now available on the different routes of prion infection, both the mechanisms underlying prion neurotoxicity and the physiologic role of PrP(C) remain unclear. By use of a novel paradigm, we have shown in a recent paper that-following a myotoxin-induced degenerative challenge-PrP(C) is implicated in the morphogenesis of the skeletal muscle of adult mice. PrP(C) accomplished this task by modulating signaling pathways central to the myogenic process, in particular the p38 kinase pathway. The possibility that PrP(C) acts in cell signaling has already been suggested after in vitro studies. Using our in vivo approach, we have instead provided proof of the physiologic relevance of PrPC commitment in signaling events, and that PrP(C) likely performed the task by controlling the activity of the enzyme (TACE) secreting the signaling TNF alpha molecule. After a brief summary of our data, here we will discuss the suggestion, arising from our and other recent findings, implying that regulation of TACE, and of other members of the protease family TACE belongs to, may be exploited by PrP(C) in different cell contexts. Notably, this advancement of knowledge on PrP(C) physiology could also shed light on the defense mechanisms against the onset of a more common neurodegenerative disorder than prion disease, such as Alzheimer disease.