Regulation of Apolipoprotein Secretion by TTYH1 and tweety in Glial Cells

项目摘要 脂质转运是中枢神经系统中脂质代谢和应激反应的组成部分。脂蛋白 是神经元和胶质细胞之间的主要细胞间脂质载体。脂质成分、运输和 脂蛋白的代谢命运在很大程度上取决于相关的载脂蛋白。功能中断 载脂蛋白导致神经变性动物模型中的神经变性表型。此外，委员会认为， 载脂蛋白E（Apolipoprotein E，APOE）基因的等位基因变异是阿尔茨海默病（Alzheimer's Disease，AD）的主要危险因素。胶质 细胞如星形胶质细胞和小胶质细胞是神经系统中加工和分泌ApoE的主要细胞类型。 系统胶质细胞还通过减轻神经元氧化应激（AD的常见标志）和神经元氧化应激（AD的常见标志）发挥保护作用。 其他神经退行性疾病。虽然载脂蛋白在脂质代谢中起着重要作用， 虽然我们对神经系统中载脂蛋白转运的认识还很有限，但我们对神经系统中载脂蛋白转运的认识还很有限。此外，本发明还提供了一种方法， 胶质细胞是否将氧化应激反应与载脂蛋白运输偶联仍有待检验。以来 细胞内囊泡区室是载脂蛋白运输所必需的，我们假设， 内溶酶体蛋白在脑中与ApoE功能性相互作用。通过检测假定的 通过对内溶酶体基因的研究，我们鉴定了在人脑中与APOE共表达的Tweety同系物1（TTYH 1）。 在哺乳动物细胞和果蝇tty突变体（TTYH 1同源物）中进行的初步研究表明， tty和TTYH 1是胶质细胞分泌载脂蛋白如ApoD和ApoE所必需的， 调节神经系统中的氧化应激。tty突变果蝇寿命缩短， 表型。我们的中心假设是tty和TTYH 1调节载脂蛋白运输， 神经胶质细胞中的氧化应激。在这项研究中，我们的目标是解决tty和TTYH 1在以下方面的作用：1）分泌 载脂蛋白从胶质细胞到循环;和2）通过载脂蛋白分泌减轻胶质细胞氧化应激。 我们的长期目标是阐明胶质细胞ApoE/D加工和分泌的具体调控途径 并揭示了AD和相关痴呆症的新治疗靶点。

Project Summary Lipid transport is integral to lipid metabolism and stress response in the central nervous system. Lipoproteins are the major intercellular lipid carrier between neurons and glia. The lipid composition, trafficking, and metabolic fate of lipoproteins are largely dependent on the associated apolipoproteins. Disrupted function of apolipoproteins result in neurodegenerative phenotypes in animal models of neurodegeneration. Furthermore, allelic variation of the Apolipoprotein E (APOE) gene is the major risk factor of Alzheimer's Disease (AD). Glial cells such as astrocytes and microglia are the major cell types that process and secret ApoE in the nervous system. Glia also serve a protective role by mitigating neuronal oxidative stress, a common hallmark of AD and other neurodegenerative diseases. While it is well established that apolipoproteins play critical roles in lipid metabolism, our understanding of apolipoprotein transport in the nervous system is still limited. In addition, whether glial cells couple oxidative stress response with apolipoprotein trafficking remains to be tested. Since intracellular vesicular compartments are required for the trafficking of apolipoproteins, we hypothesize that endolysosomal proteins functionally interact with ApoE in brain. By examining the expression profile of putative endolysosomal genes, we identify Tweety Homolog 1 (TTYH1) that co-expresses with APOE in human brain. Preliminary studies performed in mammalian cells and Drosophila mutant of tty, homolog of TTYH1, suggest that tty and TTYH1 are required for the secretion of apolipoproteins, such as ApoD and ApoE, from glia and regulating oxidative stress in the nervous system. tty mutant flies show shortened lifespan and locomotor phenotypes. Our central hypothesis is that tty and TTYH1 regulate apolipoprotein trafficking to mitigate oxidative stress in glial cells. In this proposal, we aim to address the roles of tty and TTYH1 in: 1) the secretion of apolipoprotein from glia to circulation; and 2) mitigating glial oxidative stress via apolipoprotein secretion. Our long-term goal is to delineate specific pathway that regulate ApoE/D processing and secretion in glial cells and reveal new therapeutic targets for AD and related dementias.