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Vol. 19, Issue 3, 833-842, March 2008

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Polyunsaturated Fatty Acids Influence Synaptojanin Localization to Regulate Synaptic Vesicle Recycling

Esther Marza^*, Toni Long, Adolfo Saiardi^*,, Marija Sumakovic, Stefan Eimer, David H. Hall, and Giovanni M. Lesa^*,||

*MRC Laboratory for Molecular Cell Biology, Cell Biology Unit, and ^||Department of Cell and Developmental Biology, University College London, London, WC1E 6BT, United Kingdom; Center for C. elegans Anatomy, Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461; and European Neuroscience Institute, Center for Molecular Physiology of the Brain, 37077 Goettingen, Germany

Submitted July 28, 2007; Revised November 26, 2007; Accepted December 10, 2007
Monitoring Editor: Howard Riezman

The lipid polyunsaturated fatty acids are highly enriched in synaptic membranes, including synaptic vesicles, but their precise function there is unknown. Caenorhabditis elegans fat-3 mutants lack long-chain polyunsaturated fatty acids (LC-PUFAs); they release abnormally low levels of serotonin and acetylcholine and are depleted of synaptic vesicles, but the mechanistic basis of these defects is unclear. Here we demonstrate that synaptic vesicle endocytosis is impaired in the mutants: the synaptic vesicle protein synaptobrevin is not efficiently retrieved after synaptic vesicles fuse with the presynaptic membrane, and the presynaptic terminals contain abnormally large endosomal-like compartments and synaptic vesicles. Moreover, the mutants have abnormally low levels of the phosphoinositide phosphatase synaptojanin at release sites and accumulate the main synaptojanin substrate phosphatidylinositol 4,5-bisphosphate at these sites. Both synaptobrevin and synaptojanin mislocalization can be rescued by providing exogenous arachidonic acid, an LC-PUFA, suggesting that the endocytosis defect is caused by LC-PUFA depletion. By showing that the genes fat-3 and synaptojanin act in the same endocytic pathway at synapses, our findings suggest that LC-PUFAs are required for efficient synaptic vesicle recycling, probably by modulating synaptojanin localization at synapses.

Address correspondence to: Giovanni M. Lesa (Giovanni.Lesa{at}ucl.ac.uk)

Abbreviations used: AA, arachidonic acid; ALA, -linolenic acid; DHA, docosahexaenoic acid; GABA, -aminobutyric acid; LIN, linoleic acid; LC, long chain; PtdIns, phosphatidylinositol; PUFA, polyunsaturated fatty acid; SV, synaptic vesicle; WT, wild type.

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