Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys.

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, Miquel Vila
Ann Neurol.. 2014-02-18; 75(3): 351-362
DOI: 10.1002/ana.24066

Lire sur PubMed

1. Ann Neurol. 2014 Mar;75(3):351-62. doi: 10.1002/ana.24066. Epub 2014 Feb 18.

Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology
and neurodegeneration in mice and monkeys.

Recasens A(1), Dehay B, Bové J, Carballo-Carbajal I, Dovero S, Pérez-Villalba A,
Fernagut PO, Blesa J, Parent A, Perier C, Fariñas I, Obeso JA, Bezard E, Vila M.

Author information:
(1)Neurodegenerative Diseases Research Group, Vall d’Hebron Research
Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases,
Barcelona, Spain.

Comment in
Mov Disord. 2014 Jul;29(8):988.

OBJECTIVE: 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.
METHODS: 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.
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 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.
INTERPRETATION: 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.

© 2014 Child Neurology Society/American Neurological Association.

DOI: 10.1002/ana.24066
PMID: 24243558 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus