Polyunsaturated fatty acids influence synaptojanin localization to regulate synaptic vesicle recycling.
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.
Marza
Esther
E
MRC Laboratory for Molecular Cell Biology, University College London, London, WC1E 6BT, United Kingdom.
Long
Toni
T
Saiardi
Adolfo
A
Sumakovic
Marija
M
Eimer
Stefan
S
Hall
David H
DH
Lesa
Giovanni M
GM
D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D004705:Endocytosis / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D008124:Locomotion / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D050683:R-SNARE Proteins / Q000378:metabolism; D013572:Synaptic Vesicles / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure
D015820:Cadherins; D029742:Caenorhabditis elegans Proteins; D005231:Fatty Acids, Unsaturated; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D050683:R-SNARE Proteins; C477784:fat-3 protein, C elegans; D016718:Arachidonic Acid; D004815:Epidermal Growth Factor; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase; C097702:synaptojanin; D010744:Phosphoric Monoester Hydrolases