Defined α-synuclein prion-like molecular assemblies spreading in cell culture

Background: alpha-Synuclein (alpha-syn) plays a central role in the pathogenesis of synucleinopathies, a group of neurodegenerative disorders that includes Parkinson disease, dementia with Lewy bodies and multiple system atrophy. Several findings from cell culture and mouse experiments suggest intercellular alpha-syn transfer. Results: Through a methodology used to obtain synthetic mammalian prions, we tested whether recombinant human alpha-syn amyloids can promote prion-like accumulation in neuronal cell lines in vitro. A single exposure to amyloid fibrils of human alpha-syn was sufficient to induce aggregation of endogenous alpha-syn in human neuroblastoma SH-SY5Y cells. Remarkably, endogenous wild-type alpha-syn was sufficient for the formation of these aggregates, and overexpression of the protein was not required. Conclusions: Our results provide compelling evidence that endogenous a-syn can accumulate in cell culture after a single exposure to exogenous alpha-syn short amyloid fibrils. Importantly, using alpha-syn short amyloid fibrils as seed, endogenous alpha-syn aggregates and accumulates over several passages in cell culture, providing an excellent tool for potential therapeutic screening of pathogenic alpha-syn aggregates.