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Abstract

Prion diseases are characterized by the conformational
transition of the cellular prion protein (PrPC) into an aberrant
protein conformer, designated scrapie-prion protein
(PrPSc). 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.