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.
Highlights
Conversion of the cellular prion protein (PrPC) into a conformationally altered pathogenic form, denoted PrP scrapie (PrPSc) is the central event in the pathogenesis of transmissible prion diseases [1]
While Pimpinelli et al reported a predominant localization in late endosomes of neuroblastomaderived (N2a) and hypothalamic gonadotropin releasing (GT1-7) cell lines [13], other studies have reported that in primary neurons and in N2a cells PrPC is internalized and recycled back to the cell surface, with very little being localized in lysosomes [6,7]
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) and a new variant of CJD, which is thought to be caused by ingestion of cattlederived foodstuffs contaminated with prions
Summary
Conversion of the cellular prion protein (PrPC) into a conformationally altered pathogenic form, denoted PrP scrapie (PrPSc) is the central event in the pathogenesis of transmissible prion diseases [1]. A number of studies have already attempted to identify subcellular location(s) where prion conversion occurs, mostly by analyzing PrPC and PrPSc subcellular distribution and trafficking in infected cell lines [3,4], primary neurons [5,6,7] and in the brains of infected animals [8,9,10,11,12] using different techniques. These results remain controversial and do not provide clear evidence for the involvement of any specific compartment. PrPC is found principally at the plasma membrane [5] and on vesicles resembling early endocytic or recycling vesicles [12]
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