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Sphingolipid-dependent Dscam sorting regulates axon segregation

ABSTRACT: Neurons are highly polarized cells with distinct protein compositions in axonal and dendritic compartments. Cellular mechanisms controlling polarized protein sorting have been described for mature nervous system but little is known about the segregation in newly differentiated neurons. In a forward genetic screen for regulators of Drosophila brain circuit development, we identified mutations in Serine Palmitoyltransferase (SPT), an evolutionary conserved enzyme in sphingolipid biosynthesis. Here we show that reduced levels of sphingolipids in SPT mutants cause axonal morphology defects similar to loss of cell recognition molecule Dscam. Loss- and gain-of-function studies show that neuronal sphingolipids are critical to prevent aggregation of axonal and dendritic Dscam isoforms, thereby ensuring precise Dscam localization to support axon branch segregation. Furthermore, SPT mutations causing neurodegenerative HSAN-I disorder in humans also result in formation of stable Dscam aggregates and axonal branch phenotypes in Drosophila neurons, indicating a causal link between developmental protein sorting defects and neuronal dysfunction.

INSTRUMENT(S): Liquid Chromatography MS - Alternating (LC-MS (Alternating)), Liquid Chromatography MS - alternating - reverse phase

SUBMITTER: Kristaps Klavins

PROVIDER: MTBLS825 | MetaboLights | 2019-03-29

REPOSITORIES: MetaboLights

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Project description:BACKGROUND: It has been reported that the gut microbiome is involved in the pathogenesis of uveitis, but the specific pathogenic microbes and metabolites in different types of uveitis are still unclear.METHODS: Microbiome and metabolites were detected using 16S ribosomal DNA and LC‒MS/MS (liquid chromatography tandem mass spectrometry) in 45 individuals, including 16 patients with Vogt Koyanagi Harada (VKH), 11 patients with acute anterior uveitis (AAU) and 18 healthy controls.RESULT: The diversity of intestinal microbes among the VKH, AAU and control groups was not significantly different. 13 specific microbes and 38 metabolites were detected in the VKH group, and 7 metabolites (vanillin, erythro-isoleucine, pyrimidine, 1-aminocyclopropanecarboxylic acid, beta-tocopherol, (-)-gallocatechin and N1-methyl-4-pyridone-3-carboxamide) significantly changed only in patients with VKH, which mainly acted on nicotinamide and nicotinamide metabolism and biotin metabolism (p<0.05). Compared with the VKH group, the AAU group had milder intestinal changes. Only 11 specific microbes and 29 metabolites changed in the AAU group, while these metabolites were not specific (p<0.05). These metabolites mainly acted on arachidonic acid metabolism. In addition, 3 microbes and 2 metabolites had the same changes in the VKH and AAU groups (p<0.05). Multiple correlations were found between gut microbes and metabolites in the VKH and AAU groups. 6 microbes (Pediococcus, Pseudomonas, Rhodococcus, Photobacterium, Gardnerella and Lawsonia) and 2 metabolites (pyrimidine and gallocatechin) as biomarkers could effectively distinguish patients with VKH from patients with AAU and healthy individuals, with AUC (area under the curve) values greater than 82%. 4 microbes (Lentilactobacillus, Lachnospiraceae_UCG-010, Cetobacterium, Liquorilactobacillus) could distinguish patients with AAU from patients with VKH and healthy controls with AUC>76%.CONCLUSION: Significant differences in intestinal microbes and metabolites suggest their different roles in the pathogenesis of uveitis entities. Changes in the metabolism of certain B vitamins may be involved in the pathogenesis of VKH.

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Sphingolipid-dependent Dscam sorting regulates axon segregation

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