Abstract
Prions are unconventional agents composed of misfolded prion protein that cause fatal neurodegenerative diseases in mammals. Prion strains induce specific neuropathological changes in selected brain areas. The mechanism of strain-specific cell tropism is unknown. We hypothesised that prion strains rely on different endocytic routes to invade and replicate within their target cells. Using prion permissive cells, we determined how impairment of endocytosis affects productive infection by prion strains 22L and RML. We demonstrate that early and late stages of prion infection are differentially sensitive to perturbation of clathrin- and caveolin-mediated endocytosis. Manipulation of canonical endocytic pathways only slightly influenced prion uptake. However, blocking the same routes had drastic strain-specific consequences on the establishment of infection. Our data argue that prion strains use different endocytic pathways for infection and suggest that cell type-dependent differences in prion uptake could contribute to host cell tropism.
Highlights
Prions are unconventional agents composed of misfolded prion protein that cause fatal neurodegenerative diseases in mammals
Different requirements for specific endocytosis pathways could indicate that the subcellular compartments involved in establishing productive infections differ for different strains. To this end we examined the role of canonical endocytic pathways implicated in prion uptake and establishment of chronic prion infection
PrPC in prion-permissive L929 cells localizes to the cell surface, associates with detergent-resistant membranes and is endocytosed via clathrin-mediated endocytosis
Summary
Prions are unconventional agents composed of misfolded prion protein that cause fatal neurodegenerative diseases in mammals. We hypothesised that prion strains rely on different endocytic routes to invade and replicate within their target cells. A misfolded, aggregated isoform (PrPSc) of the cellular prion protein (PrPC) is the major if not sole component of the infectious agent[2, 3]. Certain cell lines can faithfully propagate different prion strains, while other cell lines are permissive to only one strain[28, 29]. We hypothesised that prion strains use different cellular trafficking pathways for cell invasion and productive infection. Studying cellular aspects of prion replication has been notoriously difficult due to the low number of permissive cell lines and their restricted susceptibility to only certain prion strains The peculiar susceptibility of fibroblasts to different prion strains makes them suitable for elucidating basic principles of prion strain replication that so far have been unexplored
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