Abstract
Prion diseases are transmissible and fatal neurodegenerative disorders of humans and animals. They are characterized by the accumulation of PrPSc, an aberrantly folded isoform of the cellular prion protein PrPC, in the brains of affected individuals. PrPC is a cell surface glycoprotein attached to the outer leaflet of the plasma membrane by a glycosyl-phosphatidyl-inositol (GPI) anchor. Specifically, it is associated with lipid rafts, membrane microdomains enriched in cholesterol and sphinoglipids. It has been established that inhibition of endogenous cholesterol synthesis disturbs lipid raft association of PrPC and prevents PrPSc accumulation in neuronal cells. Additionally, prion conversion is reduced upon interference with cellular cholesterol uptake, endosomal export, or complexation at the plasma membrane. Altogether, these results demonstrate on the one hand the importance of cholesterol for prion propagation. On the other hand, growing evidence suggests that prion infection modulates neuronal cholesterol metabolism. Similar results were reported in Alzheimer’s disease (AD): whereas amyloid β peptide formation is influenced by cellular cholesterol, levels of cholesterol in the brains of affected individuals increase during the clinical course of the disease. In this review, we summarize commonalities of alterations in cholesterol homeostasis and discuss consequences for neuronal function and therapy of prion diseases and AD.
Highlights
Transmissible spongiform encephalopathies (TSEs) or prion diseases affect both humans and animals [1,2,3]
It was shown that a severe decrease in amyloid β (Aβ) peptide in fibroblasts of transgenic presenilin knock-out mice causes an increase of cellular cholesterol levels [167]. These results suggest that an increase in cholesterol at the plasma membrane induces an increase of Alzheimer precursor protein (APP) endocytosis which leads to formation of Aβ peptide and AICD, which in turn decreases levels of intracellular cholesterol
Prion infection and Aβ peptide accumulation interfere in neuronal cholesterol metabolism, and it appears that in both conditions cellular cholesterol levels are increased, which can be toxic for cells
Summary
Transmissible spongiform encephalopathies (TSEs) or prion diseases affect both humans and animals [1,2,3]. Like many other GPI-anchored proteins, both PrPC and PrPSc are found associated with lipid rafts [20,21], detergent resistant membrane domains (DRMs) enriched in cholesterol and glycosphingolipids [22]. Directing PrPC to non-lipid raft membrane domains by replacing the signal peptide mediating GPI-anchor attachment with transmembrane domains of other proteins prevents the formation of PrPSc [23,48]. The role of lipid rafts in PrPSc formation remains unclear These microdomains may be involved in gathering PrPC and PrPSc, contain a crucial co-factor essential for the conversion, or permit the co-internalization of PrPC and PrPSc, thereby promoting the conversion of PrPC into PrPSc (for review [39])
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