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α-Synuclein strains cause distinct synucleinopathies after local and systemic administration
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Journal Article
α-Synuclein strains cause distinct synucleinopathies after local and systemic administration
2015
Overview
Brain α-synuclein deposits are the hallmark of various distinct neurodegenerative diseases, and it is proposed that α-synuclein assemblies with different structural characteristics or 'strains' (ribbons or fibrils) could account for pathological differences between these diseases; here different human α-synuclein strains are injected into rat brain, and are shown to propagate in a strain-dependent manner and cause different pathological and neurotoxic phenotypes.
Synuclein variants linked to different pathologies
Synucleinopathies are neurodegenerative disorders characterized by α-synuclein-rich protein deposits which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. The discovery of α-synuclein assemblies with different structural characteristics has led to the hypothesis that different 'strains' could account for pathological differences between these different neurodegenerative diseases. This study reports that when different human α-synuclein strains — oligomers, ribbons or fibrils — are injected into rat brain
in vivo
, they propagate in a strain-dependent manner and cause different pathological and neurotoxic phenotypes. This work has implications for disease diagnosis and prognosis and for the prospects of developing therapeutic strategies tailored for specific synucleinopathies.
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 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
2
. 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
3
,
4
. 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/44
/ 14/19
/ 59
/ 631/378
/ 64
/ 64/86
/ 82
/ 82/51
/ 82/83
/ alpha-Synuclein - administration & dosage
/ alpha-Synuclein - classification
/ Animals
/ Female
/ Humanities and Social Sciences
/ Humans
/ letter
/ Lewy Body Disease - chemically induced
/ Lewy Body Disease - metabolism
/ Lewy Body Disease - pathology
/ Multiple System Atrophy - chemically induced
/ Multiple System Atrophy - metabolism
/ Multiple System Atrophy - pathology
/ Parkinson Disease - metabolism
/ Parkinson Disease - pathology
/ Rats
/ Science
/ Substantia Nigra - drug effects
/ Substantia Nigra - metabolism
