α-Synuclein Strains Cause Distinct Synucleinopathies After Local and Systemic Administration

Nature. 2015 Jun 18;522(7556):340-4. doi: 10.1038/nature14547. Epub 2015 Jun 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier
  • Brain / drug effects
  • Brain / metabolism
  • Female
  • Humans
  • 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*
  • Phenotype
  • Rats
  • Rats, Wistar
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • Synapses / metabolism
  • Synapses / pathology
  • alpha-Synuclein / administration & dosage*
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / classification
  • alpha-Synuclein / toxicity*

Substances

  • alpha-Synuclein