Iljina, M;
Tosatto, L;
Choi, ML;
Sang, JC;
Ye, Y;
Hughes, CD;
Bryant, CE;
... Klenerman, D; + view all
(2016)
Arachidonic acid mediates the formation of abundant alpha-helical multimers of alpha-synuclein.
Scientific Reports
, 6
, Article 33928. 10.1038/srep33928.
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Abstract
The protein alpha-synuclein (αS) self-assembles into toxic beta-sheet aggregates in Parkinson’s disease, while it is proposed that αS forms soluble alpha-helical multimers in healthy neurons. Here, we have made αS multimers in vitro using arachidonic acid (ARA), one of the most abundant fatty acids in the brain, and characterized them by a combination of bulk experiments and single-molecule Fӧrster resonance energy transfer (sm-FRET) measurements. The data suggest that ARA-induced oligomers are alpha-helical, resistant to fibril formation, more prone to disaggregation, enzymatic digestion and degradation by the 26S proteasome, and lead to lower neuronal damage and reduced activation of microglia compared to the oligomers formed in the absence of ARA. These multimers can be formed at physiologically-relevant concentrations, and pathological mutants of αS form less multimers than wild-type αS. Our work provides strong biophysical evidence for the formation of alpha-helical multimers of αS in the presence of a biologically relevant fatty acid, which may have a protective role with respect to the generation of beta-sheet toxic structures during αS fibrillation.
| Type: | Article |
|---|---|
| Title: | Arachidonic acid mediates the formation of abundant alpha-helical multimers of alpha-synuclein |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/srep33928 |
| Publisher version: | http://doi.org/10.1038/srep33928 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, SINGLE-MOLECULE FLUORESCENCE, POLYUNSATURATED FATTY-ACIDS, PARKINSONS-DISEASE, LIPID VESICLES, HUMAN BRAIN, PROTEIN, AGGREGATION, BINDING, PROTEASOME, INSIGHTS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1521886 |
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