Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein

Cremades, Nunilo; Cohen, Samuel I. A.; Deas, Emma; Abramov, Andrey Y.; Chen, Allen Y.; Orte, Ángel; Sandal, Massimo; Clarke, Richard W.; Dunne, Paul; Aprile, Francesco A.; Bertoncini, Carlos W.; Wood, Nicholas; Knowles, Tuomas P. J.; Dobson, Christopher M.; Klenerman, David

doi:10.1016/j.cell.2012.03.037

articleCellMay 1, 2012HYBRID OA

Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein

NCNunilo Cremades SISamuel I. A. Cohen EDEmma Deas AYAndrey Y. Abramov AYAllen Y. Chen

University of Cambridge · National Hospital for Neurology and Neurosurgery · +4 more institutions

PubMed

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Abstract

Here, we use single-molecule techniques to study the aggregation of α-synuclein, the protein whose misfolding and deposition is associated with Parkinson's disease. We identify a conformational change from the initially formed oligomers to stable, more compact proteinase-K-resistant oligomers as the key step that leads ultimately to fibril formation. The oligomers formed as a result of the structural conversion generate much higher levels of oxidative stress in rat primary neurons than do the oligomers formed initially, showing that they are more damaging to cells. The structural conversion is remarkably slow, indicating a high kinetic barrier for the conversion and suggesting that there is a significant…

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Keywords

Fibril
Biology
Biophysics
Alpha-synuclein
Protein aggregation
Oxidative stress
Oligomer
Protein folding

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