• Ariadna Recasens, Benjamin Dehay, Jordi Bové, Iria Carballo-Carbajal, Sandra Dovero, Ana Pérez-Villalba, Pierre-Olivier Fernagut, Javier Blesa, Annabelle Parent, Celine Perier, Isabel Fariñas, José A Obeso, Erwan Bezard, and Miquel Vila.
• Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases, Barcelona, Spain.
• Ann. Neurol. 2014 Mar 1; 75 (3): 351-62.

ObjectiveMounting evidence suggests that α-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 α-synuclein fibrils can trigger α-synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic α-synuclein may apply to PD-linked pathological α-synuclein and occur in species closer to humans.MethodsNigral LB-enriched fractions containing pathological α-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 α-synuclein derived from the same nigral PD tissue.ResultsIn 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 α-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous α-synuclein. At the onset of LB-induced degeneration, host pathological α-synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB-induced pathogenic effects required both human α-synuclein present in LB extracts and host expression of α-synuclein.Interpretationα-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 α-synuclein in different brain areas and slowly progressive axon-initiated dopaminergic nigrostriatal neurodegeneration.© 2014 Child Neurology Society/American Neurological Association.

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