脂质调控神经突触发育和功能的分子细胞机制

Lipids are major components of cellular membranes and play a fundamental role in the nervous system. Mutations in lipid biosynthetic enzymes result in many diseases including intellectual disabilities (ID). For example, mutations in acyl-CoA synthetase long-chain family member 4 (ACSL4) are associated with non-syndromic ID. We previously reported that dAcsl, the Drosophila ortholog of mammalian ACSL3 and ACSL4, inhibits neuromuscular junction (NMJ) growth. However, the underlying molecular mechanism of how lipids affect neural development and function remains poorly understood. From a genetic screen, we identified that mannosyl glucosylceramide (MacCer), a class of glycosphingolipids (GSLs), is a positive regulator of Drosophila NMJ growth. Moreover, lipidomic analysis revealed an increased level of MacCer in dAcsl mutant brains, implicating a positive role for MacCer in synaptic overgrowth in dAcsl mutants. The goal of this proposal is to elucidate the molecular mechanisms underlying the regulation of synaptic development and function of membrane lipids using multidisciplinary approaches including lipidomic analysis. This study will provide novel insights into the pathogenesis of lipid-related neurological and psychiatric disorders.

脂质是主要的细胞膜组分，且对神经系统的发育与功能至关重要。多种参与脂代谢的基因突变后导致智力低下 (ID)。例如，脂酰辅酶A合成酶长链家族成员4 (ACSL4) 突变导致非综合征型智力低下。我们发现果蝇ACSL3/4的同源基因dAcsl抑制神经肌肉突触 (NMJ) 生长。但是种类繁多的脂质如何调控突触发育和功能的分子细胞机制还远不清楚。通过遗传筛选，我们发现糖鞘脂 (GSL) 甘露糖-葡萄糖神经酰胺 (MacCer)促进NMJ突触的生长。此外，通过脂质组学分析，我们发现在dAcsl突变体神经系统中MacCer含量明显增高，提示过多的MacCer可能与突变体的突触过度生长有关。本项目将利用多学科交叉研究手段，包括脂质组学分析方法，解析脂质对神经突触发育和功能的影响及其分子细胞机制，从而加深对我们对脂代谢相关神经精神疾病发病机制的认识。

脂质作为细胞膜组分和信号分子，对神经系统的发育与功能至关重要。多种参与脂代谢的基因突变后导致神经系统疾病。但脂质种类繁多并在合成代谢通路中相互转化，哪些脂质参与调控神经发育及其相关调控机制是神经生物学领域的重大科学问题。我们以传统的模式生物果蝇为材料，通过遗传筛选，发现糖鞘脂 (GSL) 合成通路中的多个基因调控神经突触的生长。进一步的遗传分析结合脂质特异抗体染色发现GSL甘露糖-葡萄糖神经酰胺 (MacCer) 促进突触生长。GSL在生物膜上与固醇组装成脂筏。通过药物学实验结合遗传分析发现MacCer促进突触生长依赖于脂筏。许多蛋白与脂筏结合并参与信号转导，例如生长因子Wnt1/Wingless (Wg)可特异的与脂筏结合并激活信号通路促进突触生长，并且Wg信号通路的激活依赖于其与脂筏的结合。进一步的研究表明MacCer在神经突触中与Wg共定位，并正调控Wg水平从而影响Wg信号通路活性。为了进一步研究MacCer是如何与Wg相互作用的，我们通过分子模拟和脂质生化试验发现，Wg中有一个包含15个氨基酸的短肽能特异性地与MacCer结合。进一步的体内实验验证两者的结合影响MacCer与Wg共定位并调控神经突触的生长。综上所述，该研究首次发现糖鞘脂 MacCer通过调控Wg信号通路促进突触发育。