Cytoskeleton-dependent clustering of membrane-bound prion protein on the cell surface.

Prion diseases are a group of neurodegenerative disorders that infect animals and humans with proteinaceous particles called prions. Prions consist of scrapie prion protein (PrP ^Sc ), a misfolded version of the cellular prion protein (PrP ^C ). During disease progression, PrP ^Sc replicates by interacting with PrP ^C and inducing its conversion to PrP ^Sc . Attachment of PrP ^C to cellular membranes via a glycosylphosphatidylinositol (GPI) anchor is critical for the conversion of PrP ^C into PrP ^Sc . However, the mechanisms governing PrP ^C conversion and replication on the membrane remain largely unclear. Here, a site-selectively modified PrP variant equipped with a fluorescent GPI anchor mimic (PrP-GPI) was employed to directly observe PrP at the cellular membrane in neuronal SH-SY5Y cells. PrP-GPI exhibits a cholesterol-dependent membrane accumulation and a cytoskeleton-dependent mobility. More specifically, inhibition of actin polymerization reduced the diffusion of PrP-GPI indicating protein clustering, which resembles the initial step of PrP aggregation and conversion into its pathogenic isoform. An intact actin cytoskeleton might therefore prevent conversion of PrP ^C into PrP ^Sc and offer new therapeutic angles.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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