Nderstanding the neurospecificity of Prion protein signaling

The cellular prion protein PrPC is the normal counterpart of the scrapie prion protein PrPSc, the main component of the infectious agent of transmissible spongiform encephalopathies (TSEs). It is a ubiquitous cell-surface glycoprotein, abundantly expressed in neurons, which constitute the targets of TSE pathogenesis. The presence of PrPC at the surface of neurons is an absolute requirement for the development of prion diseases and corruption of PrPC function(s) within an infectious context emerges as a proximal cause for PrPSc-induced neurodegeneration. Experimental evidence gained over the past decade indicates that PrPC has the capacity to mobilize promiscuous signal transduction cascades that, notably, contribute to cell homeostasis. Beyond ubiquitous effectors, much data converge onto a neurospecificity of PrPC signaling, which may be the clue to neuronal cell demise in prion disorders. In this article, we highlight the requirement of PrPC for TSEs-associated neurodegeneration and review the current knowledge of PrPC-dependent signal transduction in neuronal cells and its implications for PrPSc-mediated neurotoxicity