To clarify the cellular mechanisms for the establishment of prion infection, we analyzed the intracellular dynamics of inoculated and newly generated abnormal isoform of prion protein (PrP(Sc)) in Neuro2a cells. Within 24h after inoculation, the newly generated PrP(Sc) was evident at the plasma membrane, in early endosomes, and in late endosomes, but this PrP(Sc) was barely evident in lysosomes; in contrast, the majority of the inoculated PrP(Sc) was evident in late endosomes and lysosomes. However, during the subsequent 48 h, the newly generated PrP(Sc) increased remarkably in early endosomes and recycling endosomes. Overexpression of wild-type and mutant Rab proteins showed that membrane trafficking along not only the endocytic-recycling pathway but also the endo-lysosomal pathway is involved in de novo PrP(Sc) generation. These results suggest that the trafficking of exogenously introduced PrP(Sc) from the endo-lysosomal pathway to the endocytic-recycling pathway is important for the establishment of prion infection.
Keywords: Endosomes; Membrane trafficking; Neurodegenerative diseases; Prions; Rab proteins.
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