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


CONCLUSIONS
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.
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases, Barcelona, Spain.
Ariadna
A
Recasens
Benjamin
B
Dehay
Jordi
J
Bové
Iria
I
Carballo-Carbajal
Sandra
S
Dovero
Ana
A
Pérez-Villalba
Pierre-Olivier
PO
Fernagut
Javier
J
Blesa
Annabelle
A
Parent
Celine
C
Perier
Isabel
I
Fariñas
José A
JA
Obeso
Erwan
E
Bezard
Miquel
M
Vila
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D016631:Lewy Bodies / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology; D008253:Macaca mulatta; D051379:Mice; D018345:Mice, Knockout; D008845:Microinjections; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D014020:Tissue Extracts / Q000737:chemistry / Q000633:toxicity*; D051844:alpha-Synuclein / Q000008:administration & dosage / Q000235:genetics / Q000302:isolation & purification / Q000633:toxicity*
D014020:Tissue Extracts; D051844:alpha-Synuclein