Glial Synaptobrevin mediates peripheral nerve insulation, neural metabolic supply, and is required for motor function
Glial Synaptobrevin mediates peripheral nerve insulation, neural metabolic supply, and is required for motor function
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DOI：
10.1002/glia.24000
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发表时间：
2021-04-02
期刊：
影响因子：
6.2
通讯作者：
Walter, Alexander M.
中科院分区：
文献类型：
--
作者：
Boehme, Mathias A.;McCarthy, Anthony W.;Walter, Alexander M.
周围神经包含感觉和运动神经元轴突，轴突被胶质细胞包裹，胶质细胞的相互作用确保功能，但缺乏分子细节。SNARE蛋白通过融合囊泡与靶细胞器介导货物的交换和分泌，但胶质SNARE如何促进外周神经功能在很大程度上是未知的。我们，在这里，确定非神经元的Synaptobrevin（Syb）作为果蝇外周神经胶质细胞的基本泡状陷阱，以隔离和代谢供应神经元。我们发现，破伤风神经毒素轻链（TeNT-LC），这有力地抑制SNARE介导的胞吐从神经元，也损害外周神经功能时，选择性地表达在神经胶质细胞，导致神经解体，轴突运输缺陷，强直性肌肉活动过度，受损的运动，和致死性。虽然TeNT-LC通过切割神经元小突触蛋白（nSyb）破坏神经功能，但它靶向神经胶质中的非神经元小突触蛋白（Syb），它以低速率切割：Syb（而不是nSyb）的神经胶质敲除表型模仿的神经胶质TeNT-LC表达，其效果被TeNT-LC不敏感的Syb突变体逆转。我们将Syb的必要性与两种不同的胶质细胞亚型联系起来：损伤神经束膜下胶质细胞中的Syb功能可能会破坏神经形态、轴突运输和运动，这可能是因为神经隔离分隔连接（SJS）无法形成，因为重要的SJ成分（如细胞粘附蛋白Neurexin-IV）被错误定位。干扰Syb在轴突环绕包裹胶质细胞的神经形态和运动完整，但受损的轴突运输，可能是因为神经代谢供应中断，由于代谢物改组单羧酸转运蛋白的错误。我们的研究确定了Syb在各种胶质细胞亚型中的关键作用，以确保适当的神经功能，动物运动和生存所需的胶质-胶质和胶质-神经相互作用。
Peripheral nerves contain sensory and motor neuron axons coated by glial cells whose interplay ensures function, but molecular details are lacking. SNARE-proteins mediate the exchange and secretion of cargo by fusing vesicles with target organelles, but how glial SNAREs contribute to peripheral nerve function is largely unknown. We, here, identify non-neuronal Synaptobrevin (Syb) as the essential vesicular SNARE in Drosophila peripheral glia to insulate and metabolically supply neurons. We show that tetanus neurotoxin light chain (TeNT-LC), which potently inhibits SNARE-mediated exocytosis from neurons, also impairs peripheral nerve function when selectively expressed in glia, causing nerve disintegration, defective axonal transport, tetanic muscle hyperactivity, impaired locomotion, and lethality. While TeNT-LC disrupts neural function by cleaving neuronal Synaptobrevin (nSyb), it targets non-neuronal Synaptobrevin (Syb) in glia, which it cleaves at low rates: Glial knockdown of Syb (but not nSyb) phenocopied glial TeNT-LC expression whose effects were reverted by a TeNT-LC-insensitive Syb mutant. We link Syb-necessity to two distinct glial subtypes: Impairing Syb function in subperineurial glia disrupted nerve morphology, axonal transport, and locomotion, likely, because nerve-isolating septate junctions (SJs) could not form as essential SJ components (like the cell adhesion protein Neurexin-IV) were mistargeted. Interference with Syb in axon-encircling wrapping glia left nerve morphology and locomotion intact but impaired axonal transport, likely because neural metabolic supply was disrupted due to the mistargeting of metabolite shuffling monocarboxylate transporters. Our study identifies crucial roles of Syb in various glial subtypes to ensure glial-glial and glial-neural interplay needed for proper nerve function, animal motility, and survival.