α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion...

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 (PrP^C) in mediating the uptake and the spread of recombinant α-Syn amyloids. The in vitro data revealed that the presence of PrP^C fosters the higher uptake of α-Syn amyloid fibrils, which was also confirmed 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 (PrP^Sc) in vitro and ex vivo, indicating a link between the two proteins. Indeed, whilst PrP^C is mediating the internalization of α-Syn amyloids, PrP^Sc 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.