Alpha-synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities

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DOI

  • Parvez Alam
  • Luc Bousset, Institute Francois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, 18 Route du Panorama, 92265, Fontenay-Aux-Roses cedex, France.
  • ,
  • Ronald Melki, Institute Francois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, 18 Route du Panorama, 92265, Fontenay-Aux-Roses cedex, France.
  • ,
  • Daniel E Otzen

This review article provides an overview of the different species that alpha-synuclein (αSN) aggregates can populate. It also attempts to reconcile conflicting views regarding the cytotoxic roles of oligomers versus fibrils. αSN, while highly dynamic in the monomeric state, can access a large number of different assembly states. Depending on assembly conditions, these states can interconvert over different time scales. The fibrillar state is the most thermodynamically favoured due to the many stabilizing interactions formed between each monomeric unit, but different fibillar types form at different rates. The end distribution is likely to reflect kinetic partitioning as much as thermodynamic equilibra. In addition, metastable oligomeric species, some of which are on-pathway and others off-pathway, can be populated for remarkably long periods of time. Chemical modifications (phosphorylation, oxidation, covalent links to ligands etc) perturb these physical interconversions and invariably destabilize the fibrillar state, leading to small prefibrillar assemblies which can coalesce into amorphous states. Both oligomeric and fibrillar species have been shown to be cytotoxic although firm conclusions require very careful evaluation of particle concentrations and is complicated by the great variety and heterogeneity of different experimentally observed states. The mechanistic relationship between oligomers and fibrils remains to be clarified, both in terms of assembly of oligomers into fibrils and potential dissolution of fibrils into oligomers. While oligomers are possibly implicated in the collapse of neuronal homeostasis, the fibrillar state(s) appears to be the most efficient at propagating itself both in vitro and in vivo, pointing to critical roles for multiple different aggregate species in the progression of Parkinson's Disease. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalJournal of Neurochemistry
ISSN0022-3042
DOIs
Publication statusE-pub ahead of print - 29 Jun 2019
Externally publishedYes

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