Skip to Main content Skip to Navigation
Journal articles

$\alpha$‐synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities

Abstract : This review article provides an overview of the different species that $\alpha$-synuclein aggregates can populate. It also attempts to reconcile conflicting views regarding the cytotoxic roles of oligomers versus fibrils. $\alpha$-synuclein, 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 timescales. The fibrillar state is the most thermodynamically favored due to the many stabilizing interactions formed between each monomeric unit, but different fibrillar 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 inter-conversions 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
Document type :
Journal articles
Complete list of metadatas

Cited literature [120 references]  Display  Hide  Download

https://hal-cea.archives-ouvertes.fr/cea-02279218
Contributor : Mehdi Kabani <>
Submitted on : Tuesday, December 10, 2019 - 3:07:56 PM
Last modification on : Friday, July 3, 2020 - 11:52:03 AM
Long-term archiving on: : Wednesday, March 11, 2020 - 8:37:51 PM

File

Alam_et_al-2019-Journal_of_Neu...
Publication funded by an institution

Identifiers

Collections

Citation

Parvez Alam, Luc Bousset, Ronald Melki, Daniel Otzen. $\alpha$‐synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities. Journal of Neurochemistry, Wiley, 2019, 150 (5), pp.522-534. ⟨10.1111/jnc.14808⟩. ⟨cea-02279218⟩

Share

Metrics

Record views

89

Files downloads

200