Title: α-Synuclein strains cause distinct synucleinopathies after local and systemic administration
Authors: Peelaerts, Wouter
Bousset, L
Van der Perren, Anke
Moskalyuk, A
Pulizzi, R
Giugliano, M
Van Den Haute, Chris
Melki, R #
Baekelandt, Veerle # ×
Issue Date: 18-Jun-2015
Publisher: Nature Publishing Group
Series Title: Nature vol:522 issue:7556 pages:340-344
Article number: doi:10.1038/nature14547
Abstract: Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions. The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton α-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial α-synuclein (α-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal α-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies. The discovery of α-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies. In this study we show that α-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined α-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that α-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 α-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct α-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.
ISSN: 0028-0836
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group for Neurobiology and Gene Therapy
× corresponding author
# (joint) last author

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