OBJECTIVE: Mounting evidence suggests that alpha-synuclein, a major protein component of Lewy bodies (LB), may be responsible for initiating and spreading the pathological process in Parkinson disease (PD). Supporting this concept, intracerebral inoculation of synthetic recombinant alpha-synuclein fibrils can trigger alpha-synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic alpha-synuclein may apply to PD-linked pathological alpha-synuclein and occur in species closer to humans. METHODS: Nigral LB-enriched fractions containing pathological alpha-synuclein were purified from postmortem PD brains by sucrose gradient fractionation and subsequently inoculated into the substantia nigra or striatum of wild-type mice and macaque monkeys. Control animals received non-LB fractions containing soluble alpha-synuclein derived from the same nigral PD tissue. RESULTS: In both mice and monkeys, intranigral or intrastriatal inoculations of PD-derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. No neurodegeneration was observed in animals receiving non-LB fractions from the same patients. In LB-injected animals, exogenous human alpha-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous alpha-synuclein. At the onset of LB-induced degeneration, host pathological alpha-synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB-induced pathogenic effects required both human alpha-synuclein present in LB extracts and host expression of alpha-synuclein. INTERPRETATION: alpha-Synuclein species contained in PD-derived LB are pathogenic and have the capacity to initiate a PD-like pathological process, including intracellular and presynaptic accumulations of pathological alpha-synuclein in different brain areas and slowly progressive axon-initiated dopaminergic nigrostriatal neurodegeneration.