The role of the prion protein in the internalization of α-synuclein amyloids

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein amyloids in several regions of the brain. α-Synuclein fibrils are able to spread via cell-to-cell transfer, and once inside the cells, they can template the misfolding and aggregation of the endogenous α-synuclein. Multiple mechanisms have been shown to participate in the process of propagation: endocytosis, tunneling nanotubes and macropinocytosis. Recently, we published a research showing that the cellular form of the prion protein (PrPC) acts as a receptor for α-synuclein amyloid fibrils, facilitating their internalization through and endocytic pathway. This interaction occurs by a direct interaction between the fibrils and the N-terminal domain of PrPC. In cell lines expressing the pathological form of PrP (PrPSc), the binding between PrPCand α-synuclein fibrils prevents the formation and accumulation of PrPSc, since PrPCis no longer available as a substrate for the pathological conversion templated by PrPSc. On the contrary, PrPScdeposits are cleared over passages, probably due to the increased processing of PrPCinto the neuroprotective fragments N1 and C1. Starting from these data, in this work we present new insights into the role of PrPCin the internalization of protein amyloids and the possible therapeutic applications of these findings.