Identification of an Intracellular Site of Prion Conversion

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Abstract
Prion diseases are fatal, neurodegenerative disorders in humans and animals and are characterized by the accumulation of an abnormally folded isoform of the cellular prion protein (PrPC), denoted PrPSc, which represents the major component of infectious scrapie prions. Characterization of the mechanism of conversion of PrPC into PrPSc and identification of the intracellular site where it occurs are among the most important questions in prion biology. Despite numerous efforts, both of these questions remain unsolved. We have quantitatively analyzed the distribution of PrPC and PrPSc and measured PrPSc levels in different infected neuronal cell lines in which protein trafficking has been selectively impaired. Our data exclude roles for both early and late endosomes and identify the endosomal recycling compartment as the likely site of prion conversion. These findings represent a fundamental step towards understanding the cellular mechanism of prion conversion and will allow the development of new therapeutic approaches for prion diseases. The misfolded form (PrPSc or prion) of the naturally occuring prion protein (PrPC or cellular PrP) is responsible for neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE) (also known as ‘mad cow disease’) and a new variant of CJD (vCJD), which is thought to be caused by ingestion of cattle-derived foodstuffs contaminated with prions. These diseases are characterized by the accumulation of protein deposits in the central nervous system (CNS). However, unlike other neurodegenerative diseases, prion diseases are infectious and prions are able to propagate in a chain reaction by imposing their malconformed state onto the properly folded cellular proteins. Understanding where the conversion of PrPC into PrPSc occurs in cells has been an unsolved question until now. By analysing the intracellular localization of PrPC and PrPSc and measuring the levels of PrPSc produced in infected neuronal cell lines under conditions in which intracellular trafficking of the protein is impaired, we found that prion conversion occurs in the endosomal recycling compartment (ERC) where it transits after being internalized from the cell surface. This study will help to clarify the cellular mechanism of the disease and it opens the way to new therapeutic strategies aimed at the conversion compartment.