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February 15, 2011Proceedings of the National Academy of SciencesOpen Access

In vivo demonstration that α-synuclein oligomers are toxic

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Authors

BWBeate WinnerFriedrich-Alexander-Universität Erlangen-NürnbergRJRoberto JappelliSalk Institute for Biological StudiesSMSamir K. MajiIndian Institute of Technology Bombay

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Overview

Experimental rat study reveals that alpha-synuclein oligomers cause severe dopaminergic neuron loss in the substantia nigra, indicating that pre-fibrillar intermediates drive neurotoxicity.

Key Points

  • Determine whether alpha-synuclein oligomers or mature amyloid fibrils serve as the primary drivers of in vivo dopaminergic neurotoxicity in Parkinson disease.
  • Engineered alpha-synuclein mutants that selectively promote either oligomer accumulation (E57K, E35K) or rapid amyloid fibril formation.
  • Delivered mutant constructs into the rat substantia nigra using a lentivirus delivery system to assess dopaminergic neuron loss.
  • Oligomer-forming alpha-synuclein variants (E57K and E35K) caused the most severe dopaminergic neuronal loss in the substantia nigra.
  • Variants that rapidly assembled into mature fibrils exhibited markedly lower neurotoxicity compared to oligomeric intermediates.
  • Alpha-synuclein oligomers displayed toxicity in vivo accompanied by potential membrane-disrupting activity.

Cite This Study

Winner et al. (2011) studied this question.

synapsesocial.com/papers/69d7239a523bf2ea07f50904https://doi.org/10.1073/pnas.1100976108
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