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), a misfolded version of the cellular prion protein (PrP). During disease progression, PrP replicates by interacting with PrP and inducing its conversion to PrP. Attachment of PrP to cellular membranes via a glycosylphosphatidylinositol (GPI) anchor is critical for the conversion of PrP into PrP. However, the mechanisms governing PrP 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 into PrP and offer new therapeutic angles.