Abstract
Prion diseases are characterized by the conformational transition of the cellular prion protein (PrP(C)) into an aberrant protein conformer, designated scrapie-prion protein (PrP(Sc)). A causal link between protein misfolding and neurodegeneration has been established for a variety of neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease and polyglutamine diseases, but there is an ongoing debate about the nature of the neurotoxic species and how non-native conformers can damage neuronal populations. PrP is normally imported into the endoplasmic reticulum (ER) and targeted to the outer leaflet of the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. However, several conditions, such as ER stress or some pathogenic mutations in the PrP gene, can induce the mislocalization of PrP in the cytosol, where it has a neurotoxic potential as demonstrated in cell culture and transgenic mouse models. In this review we focus on intrinsic factors and cellular pathways implicated in the import of PrP into the ER and its mistargeting to the cytosol. The findings summarized here not only reveal a complex regulation of the biogenesis of PrP, but also provide interesting new insight into toxic activities of pathogenic protein conformers and quality control pathways of ER-targeted proteins.
Highlights
Prion diseases are a group of transmissible neurodegenerative disorders including Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS) in humans, scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in free-ranging deer
A hallmark of prion diseases is the conversion of the cellular prion protein PrPC into its misfolded isoform, termed PrPSc
Transgenic mouse models revealed that several PrP mutants can induce neuronal cell death in the absence of infectious prion propagation (Baumann et al, 2007; Chiesa et al, 1998; Flechsig et al, 2003; Hegde et al, 1998; Li et al, 2007; Ma et al, 2002; Muramoto et al, 1997; Shmerling et al, 1998)
Summary
Prion diseases are a group of transmissible neurodegenerative disorders including Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS) in humans, scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in free-ranging deer. Employing in vitro models Lingappa and coworkers demonstrated that during import into the ER, PrP can attain two different transmembrane topologies with either the N- or C-terminal domain facing the cytosol (Yost et al, 1990) (see below). The proteasome mediates post-translational degradation of non-native proteins generated in the ER as part of a quality control system, designated ER-associated degradation (ERAD) This pathway involves recognition of non-native polypeptides by ER-resident chaperones and retrograde transport to the cytosol where proteasomal degradation occurs ER import can be mediated by a remarkably diverse set of signal sequences, and it has been demonstrated for various secretory pathway proteins that translocation efficiency is regulated in a signal peptide sequence-specific manner Due to the relatively low hydrophobicity index (Kyte-Doolittle) of the signal peptide, PrP was targeted to the ER via a post-translational pathway in yeast cells. We have recently shown that the HD promotes dimer formation of PrP, which is associated with its stress-protective activity (Rambold et al, 2008)
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