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Arachidonic acid mediates the formation of abundant alpha-helical multimers of alpha-synuclein

Published version
Peer-reviewed

Type

Article

Change log

Authors

Iljina, Marija 
Tosatto, Laura 
Choi, Minee L 
Sang, Jason C 

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.

Description

Keywords

0601 Biochemistry and Cell Biology, 1109 Neurosciences, Biomedical, Basic Science, Parkinson's Disease, Neurodegenerative, Brain Disorders, Biotechnology, Neurosciences, Neurological, 2.1 Biological and endogenous factors

Journal Title

Scientific Reports

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

6

Publisher

Nature Publishing Group
Sponsorship
Alzheimer's Research Trust (ARUK-IRG2014-13)
Wellcome Trust (101585/Z/13/Z)
M.I. acknowledges Dr. Tayyeb-Hussain Scholarship. L.T. has been recipient of a grant PAT Post Doc Outgoing 2009 7th Framework Program Marie Curie COFUND actions. C.D.H. and C.E.B. acknowledge funding from Alzheimer’s Research UK. Augustus Newman Foundation is acknowledged.