Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys
Version of Record online: 18 FEB 2014
© 2014 Child Neurology Society/American Neurological Association
Annals of Neurology
Volume 75, Issue 3, pages 351–362, March 2014
How to Cite
Recasens, A., Dehay, B., Bové, J., Carballo-Carbajal, I., Dovero, S., Pérez-Villalba, A., Fernagut, P.-O., Blesa, J., Parent, A., Perier, C., Fariñas, I., Obeso, J. A., Bezard, E. and Vila, M. (2014), Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol., 75: 351–362. doi: 10.1002/ana.24066
- Issue online: 1 APR 2014
- Version of Record online: 18 FEB 2014
- Accepted manuscript online: 16 NOV 2013 06:17AM EST
- Manuscript Accepted: 12 NOV 2013
- Manuscript Revised: 30 OCT 2013
- Manuscript Received: 9 AUG 2013
Mounting 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.
Nigral 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.
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 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.
α-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. ANN NEUROL 2014;75:351–362