Traffic of prion protein between different compartments on the neuronal surface, and the propagation of prion disease

Abstract

The key mechanism in prion disease is the conversion of cellular prion protein into an altered, pathogenic conformation, in which cellular mechanisms play a poorly understood role. Both forms of prion protein are lipid-anchored and reside in rafts that appear to protect the native conformation against conversion. Neurons rapidly traffic their cellular prion protein out of its lipid rafts to be endocytosed via coated pits before recycling back to the cell surface. It is argued in this review that understanding the mechanism of this trafficking holds the key to understanding the cellular role in the conformational conversion of prion protein.

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

“…PrP C trafficking also influences its conversion into PrP Sc and disruption of the normal trafficking of PrP C seems to be a common mechanism for several classes of PrP Sc inhibitors (23,46). Notably, the hemin concentration that effectively altered PrP C trafficking (ϳ3 M) also reduced the formation of PrP Sc in scrapie-infected cell cultures (data not shown).…”

Endocytosis of Prion Protein Is Required for ERK1/2 Signaling Induced by Stress-Inducible Protein 1

“…Despite reports suggesting internalization of PrP C via caveolae (Peters et al, 2003), overwhelming evidence favors a model of endocytosis of PrP C via clathrincoated vesicles (Shyng et al, 1994;Sunyach et al, 2003;. Recently, an essential role in the endocytosis of PrP C has been ascribed to the low-density lipoprotein receptor-like protein (LRP1) (Morris et al, 2006;Taylor and Hooper, 2006;Parkyn et al, 2008), by allowing PrP C to enter clathrin-coated vesicles. In addition, LRP1 appears to have a role in the surface trafficking of PrP C (Parkyn et al, 2008).…”

Prion Protein Modulates Monoaminergic Systems and Depressive-like Behavior in Mice

“…The prion protein is mainly, albeit not exclusively, expressed at the surface of nerve and immune cells and, similar to other glycosylphosphatidylinositol-anchored proteins, PrP C associates with lipid rafts amid continuous trafficking around distinct plasma membrane domains and intracellular vesicles (8,9). Experimental studies show that PrP C participates in events such as cell proliferation, differentiation, and survival through various signaling pathways (5,6).…”