Prion-like spreading of pathological α-synuclein in brain

alpha-Synuclein is the major component of filamentous inclusions that constitute the defining characteristic of neurodegenerative alpha-synucleinopathies. However, the molecular mechanisms underlying alpha-synuclein accumulation and spread are unclear. Here we show that intracerebral injections of sarkosyl-insoluble alpha-synuclein from brains of patients with dementia with Lewy bodies induced hyperphosphorylated alpha-synuclein pathology in wild-type mice. Furthermore, injection of fibrils of recombinant human and mouse alpha-synuclein efficiently induced similar alpha-synuclein pathologies in wild-type mice. C57BL/6J mice injected with alpha-synuclein fibrils developed abundant Lewy body/Lewy neurite-like pathology, whereas mice injected with soluble alpha-synuclein did not. Immunoblot analysis demonstrated that endogenous mouse alpha-synuclein started to accumulate 3 months after inoculation, while injected human alpha-synuclein fibrils disappeared in about a week. These results indicate that alpha-synuclein fibrils have prion-like properties and inoculation into wild-type brain induces alpha-synuclein pathology in vivo. This is a new mouse model of sporadic alpha-synucleinopathy and should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy.