期刊
NATURE
卷 522, 期 7556, 页码 340-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature14547
关键词
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资金
- FWO-Vlaanderen [G.0768.10, G.0927.14]
- IWT-Vlaanderen [IWT SBO/80020 Neuro-TARGET, SBO/110068 OPTOBRAIN, SBO/130065 MIRIAD]
- FP7 RTD project MEFOPA [HEALTH-2009-241791]
- FP7 RTD project INMiND [HEALTH-F2-2011-278850]
- KU Leuven [OT/08/052A, OT/14/120, IMIR PF/10/017]
- Agence Nationale de la Recherche [ANR-09-MNPS-013-01, ANR-11-BSV8-021-01]
- Centre National de la Recherche Scientifique
- 'Coup d'Elan a la Recherche Francaise' award from Fondation Bettencourt Schueller
- EC-FP7 (Marie Curie Initial Training Network NAMASEN) [264872]
- ICT-FET project ENLIGHTENMENT
- ICT-FET project BRAINLEAP [284801, 306502]
- Belgian Science Policy Office [IUAP-VII/20]
Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions(1). The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton alpha-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial alpha-synuclein (alpha-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal alpha-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies(2). The discovery of alpha-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinicopathological traits within synucleinopathies(3,4). In this study we show that alpha-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined alpha-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that alpha-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that alpha-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct alpha-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.
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