title: α-Synuclein strains cause distinct synucleinopathies after local and systemic administration.
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.
authors.affiliation: KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, 3000 Leuven, Belgium.
authors.forename: W
authors.initials: W
authors.lastname: Peelaerts
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: L
authors.initials: L
authors.lastname: Bousset
authors.affiliation: KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, 3000 Leuven, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Van der Perren
authors.affiliation: Theoretical Neurobiology &Neuroengineering Laboratory, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Moskalyuk
authors.affiliation: Theoretical Neurobiology &Neuroengineering Laboratory, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Pulizzi
authors.affiliation: 1] Theoretical Neurobiology &Neuroengineering Laboratory, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium [2] Department of Computer Science, University of Sheffield, S1 4DP Sheffield, UK [3] Brain Mind Institute, Swiss Federal Institute of Technology of Lausanne, 1015 Lausanne, Switzerland [4] Neuro-Electronics Research Flanders (NERF), 3001 Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Giugliano
authors.affiliation: 1] KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, 3000 Leuven, Belgium [2] KU Leuven, Leuven Viral Vector Core, 3000 Leuven, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Van den Haute
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: R
authors.initials: R
authors.lastname: Melki
authors.affiliation: KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, 3000 Leuven, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Baekelandt
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D019578:Multiple System Atrophy / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000008:administration & dosage* / Q000737:chemistry / Q000145:classification / Q000633:toxicity*
chemical_list: D051844:alpha-Synuclein