The precise molecular mechanism of how misfolded α-synuclein (α-Syn) accumulates and spreads
in synucleinopathies is still unknown. Here, we show the role of the cellular prion protein (PrPC) in
mediating the uptake and the spread of recombinant α-Syn amyloids. The in vitro data revealed that
the presence of PrPC fosters the higher uptake of α-Syn amyloid fbrils, which was also confrmed in vivo
in wild type (Prnp+/+) compared to PrP knock-out (Prnp−/−) mice. Additionally, the presence of α-Syn
amyloids blocked the replication of scrapie prions (PrPSc) in vitro and ex vivo, indicating a link between
the two proteins. Indeed, whilst PrPC is mediating the internalization of α-Syn amyloids, PrPSc is not
able to replicate in their presence. This observation has pathological relevance, since several reported
case studies show that the accumulation of α-Syn amyloid deposits in Creutzfeldt-Jakob disease
patients is accompanied by a longer disease course.
