Abstract
PrPSc, a misfolded, aggregation-prone isoform of the cellular prion protein (PrPC), is the infectious prion agent responsible for incurable brain diseases such as scrapie of sheep, bovine spongiform encephalopathy, and its human counterpart, variant Creutzfeldt-Jakob disease. In these disorders, collectively known as prion diseases, exogenous PrPSc propagates in the infected host by imprinting its aberrant conformation onto endogenous PrPC, eventually triggering a rapidly progressing neurodegenerative process that invariably leads to death. But what is the function of PrPC besides serving as a substrate for the generation of PrPSc? And how does PrPC misfolding cause neurological disease?
Highlights
It is synthesized in the endoplasmic reticulum (ER), where it undergoes oxidative folding, N-linked glycosylation, and addition of a glycosyl-phosphatidyl-inositol (GPI) anchor that attaches the protein’s C terminus to the lipid bilayer
Based on the analysis of mild phenotypic traits that develop in PrPC knockout mice and on cell culture studies, mammalian PrPC has been assigned roles in many biological processes, including neurotransmission, olfaction, proliferation and differentiation of neural precursor cells, myelin maintenance, copper and zinc ion transport, and calcium homeostasis, as well as neuroprotective activities against several toxic insults, such as oxidative and excitotoxic damage [2,3,4]
Extracellular PrPSc kills only neurons that express PrPC. This was first shown by a neurografting experiment in which neural tissue from PrPC-expressing mice was transplanted into the brains of PrP knockout mice, which do not replicate prions since they lack the PrPC substrate for PrPSc production [7]
Summary
PrPSc, a misfolded, aggregation-prone isoform of the cellular prion protein (PrPC), is the infectious prion agent responsible for incurable brain diseases such as scrapie of sheep, bovine spongiform encephalopathy, and its human counterpart, variant Creutzfeldt-Jakob disease. In these disorders, collectively known as prion diseases, exogenous PrPSc propagates in the infected host by imprinting its aberrant conformation onto endogenous PrPC, eventually triggering a rapidly progressing neurodegenerative process that invariably leads to death. What is the function of PrPC besides serving as a substrate for the generation of PrPSc? How does PrPC misfolding cause neurological disease?
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