title: Acsl, the Drosophila ortholog of intellectual-disability-related ACSL4, inhibits synaptic growth by altered lipids.
abstract: Nervous system development and function are tightly regulated by metabolic processes, including the metabolism of lipids such as fatty acids. Mutations in long-chain acyl-CoA synthetase 4 (ACSL4) are associated with non-syndromic intellectual disabilities. We previously reported that Acsl, the Drosophila ortholog of mammalian ACSL3 and ACSL4, inhibits neuromuscular synapse growth by suppressing bone morphogenetic protein (BMP) signaling. Here, we report that Acsl regulates the composition of fatty acids and membrane lipids, which in turn affects neuromuscular junction (NMJ) synapse development. Acsl mutant brains had a decreased abundance of C16:1 fatty acyls; restoration of Acsl expression abrogated NMJ overgrowth and the increase in BMP signaling. A lipidomic analysis revealed that Acsl suppressed the levels of three lipid raft components in the brain, including mannosyl glucosylceramide (MacCer), phosphoethanolamine ceramide and ergosterol. The MacCer level was elevated in Acsl mutant NMJs and, along with sterol, promoted NMJ overgrowth, but was not associated with the increase in BMP signaling in the mutants. These findings suggest that Acsl inhibits NMJ growth by stimulating C16:1 fatty acyl production and concomitantly suppressing raft-associated lipid levels.
authors.affiliation: State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|Sino-Danish College, Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Huang
authors.affiliation: State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Sin Man
authors.initials: SM
authors.lastname: Lam
authors.affiliation: State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guanghou
authors.initials: G
authors.lastname: Shui
authors.affiliation: State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China yqzhang@genetics.ac.cn.
authors.forename: Yong Q
authors.identifier: 0000-0003-0581-4882
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D044943:Fatty Acid Desaturases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D008607:Intellectual Disability / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry*; D021962:Membrane Microdomains / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013261:Sterols / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D002518:Ceramides; D029721:Drosophila Proteins; D005227:Fatty Acids; D008055:Lipids; D013261:Sterols; D044943:Fatty Acid Desaturases; C408225:desat1 protein, Drosophila; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
keywords: ACSL; Fatty acid; Lipid; Long-chain acyl-CoA synthetase; Neuromuscular junction; Synaptic growth