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: W Peelaerts, L Bousset, A Van der Perren, A Moskalyuk, R Pulizzi, M Giugliano, C Van den Haute, R Melki, V Baekelandt
• Journal: Nature (Nature) Vol. 522 Issue 7556 Pg. 340-4 (Jun 18 2015) ISSN: 1476-4687 [Electronic] England
• PMID: 26061766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• alpha-Synuclein

Topics

• Animals
• Blood-Brain Barrier
• Brain (drug effects, metabolism)
• Female
• Humans
• Lewy Body Disease (chemically induced, metabolism, pathology)
• Multiple System Atrophy (chemically induced, metabolism, pathology)
• Parkinson Disease (metabolism, pathology)
• Phenotype
• Rats
• Rats, Wistar
• Substantia Nigra (drug effects, metabolism, pathology)
• Synapses (metabolism, pathology)
• alpha-Synuclein (administration & dosage, chemistry, classification, toxicity)