Publication
Title
-Synuclein strains cause distinct synucleinopathies after local and systemic administration
Author
Abstract
Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases but differences in protein components and affected brain regions1. The molecular hallmark of synucleinopathies such as Parkinsons Disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) are mega-dalton α-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial α-synuclein (αSYN) filamentous deposits are prominent in MSA while neuronal αSYN inclusions are found in PD and DLB2. The recent discovery of αSYN assemblies with different structural characteristics or strains has led to the hypothesis that strains could provide an explanation for the different clinico-pathological traits within synucleinopathies3,4. In this study we show that αSYN strain conformation and seeding propensity lead to distinct histopathological and behavioral phenotypes. We assess the properties of structurally well-defined αSYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that αSYN strains amplify in vivo. Fibrils appear as the major toxic species resulting in progressive motor impairment and cell death, while ribbons cause a distinct histopathological phenotype displaying PD and MSA traits. Additionally, we show that αSYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct αSYN strains display differential seeding capacities inducing strain-specific pathology and neurotoxic phenotypes.
Language
English
Source (journal)
Nature. - London, 1869, currens
Publication
London : MacMillan , 2015
ISSN
0028-0836 [print]
1476-4687 [online]
DOI
10.1038/NATURE14547
Volume/pages
522 :7556 (2015) , p. 340-344
ISI
000356425400053
Pubmed ID
26061766
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Project info
Integrated platform for target identification, validation and drug discovery with applications for neurodegenerative diseases (Neuro-TARGET).
Imaging of Neuroinflammation in Neurodegenerative Diseases (INMIND).
MEFOPA:European Project on Mendelian Forms of Parkinsons Disease
Neuroelectronics and nanotechnology: towards a multidisciplinary approach for the science and engineering of neuronal networks (NAMASEN).
Exploring the neural coding in behaving animals by novel optogenetic, high-density microrecordings and computational approaches: Towards cognitive Brain-Computer Interfaces (ENLIGHTENMENT).
A quantum leap: from a spike-centered brrain universe to its underlying synaptic landscape (BRAINLEAP).
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 11.05.2015
Last edited 19.11.2024
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