The role of mitochondrial stress response in alcohol-mediated neurotoxicity

线粒体应激反应在酒精介导的神经毒性中的作用

• 批准号: 10708781
• 负责人: Hongkyun Kim
• 金额: $ 18.53万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10708781
• 关键词: Alcohol consumption; Alcohol dependence; Alcohols; Brain Injuries; Caenorhabditis elegans; Cell Death; Cellular Stress; Cerebellar Diseases; Chronic; Cognition Disorders; Cytoplasm; Data; Development; Ethanol toxicity; Exhibits; Functional disorder; Genes; Genetic; Genetic Models; Genetic study; Health; Hepatic Encephalopathy; Homologous Gene; Human; Impaired cognition; Impairment; Insulin-Like Growth Factor Receptor; Investigation; Lipids; Malnutrition; Mammals; Mediating; Mitochondria; Molecular; Motor; Movement; Movement Disorders; Nematoda; Nervous System; Nervous System Trauma; Neurons; Neurosecretory Systems; Nutritional; Oxidative Stress Induction; Pathogenicity; Pathologic; Pathway interactions; Peripheral; Population; Proteins; Role; Signal Induction; Signal Pathway; Signal Transduction; Testing; Therapeutic; Thiamine Deficiency; Time; Tissues; Toxic effect; Tremor; alcohol consequences; alcohol effect; alcohol exposure; alcohol misuse; alcohol use disorder; biological adaptation to stress; chronic alcohol ingestion; druggable target; genetic analysis; genetic manipulation; mitochondrial dysfunction; model organism; motor impairment; neural; neurotoxicity; neurotransmission; problem drinker; proteostasis; response; transcription factor

Chronic, excessive alcohol use causes regional structural brain damage and cognitive disorders. Chronic alcohol misuse is also associated with a wide array of movement impairments. Chronic alcohol consumption alone, or together with alcoholic hepatic encephalopathy, can cause various types of tremor, asterixis, and cerebellar dysfunction. While alcohol-induced brain damage has been explained by alcohol’s effects on neural excitability or nutritional deficiency, we do not fully understand the pathogenic mechanism at the molecular and cellular levels by which alcohol exerts its toxicity and damages the nervous system. The nematode C. elegans is an amenable model organism that can be used for dissecting the pathological mechanism of alcoholic neurotoxicity. Our study in C. elegans shows that while alcohol strongly induces many conserved cellular stress responses, its main toxic effects are centered on mitochondrial function. Remarkably, we find that perpetual mitochondrial unfolded protein response (UPRmt) spares from a motor function deficit caused by chronic alcohol exposure. Moreover, a genetic manipulation that specifically induces neuron-specific UPRmt activation is sufficient to protect against alcohol-mediated movement impairment. We hypothesize that activation of a branch of UPRmt in a select neural population protects against alcoholic movement disorders. To test this hypothesis, we propose two specific aims: aim 1 will investigate how perpetual UPRmt protects against alcohol-mediated movement impairment; and aim 2 will identify the mechanism by which neuronal UPRmt leads to the protection against alcohol-mediated movement impairment. A detailed analysis of alcohol-mediated UPRmt and its intra- and intercellular signaling in the context of alcohol-mediated movement impairment will lead to effective druggable targets that protect against, or ameliorate, alcoholic movement impairment.

长期过量饮酒会导致区域结构性脑损伤和认知障碍。慢性的 滥用酒精还与多种运动障碍有关。长期饮酒 单独或与酒精性肝性脑病一起，可引起各种类型的震颤、扑翼样震颤和 小脑功能障碍。虽然酒精引起的脑损伤可以通过酒精对神经的影响来解释 兴奋性或营养缺乏，我们尚未完全了解其分子和机制上的致病机制。 酒精发挥毒性并损害神经系统的细胞水平。线虫 秀丽隐杆线虫 是一种适合的模型生物，可用于剖析酒精的病理机制 神经毒性。我们对秀丽隐杆线虫的研究表明，虽然酒精强烈诱导许多保守的细胞 应激反应，其主要毒性作用集中在线粒体功能上。值得注意的是，我们发现 永久性线粒体未折叠蛋白反应（UPRmt）可避免由以下原因引起的运动功能缺陷 长期接触酒精。此外，特异性诱导神经元特异性 UPRmt 的基因操作 激活足以防止酒精介导的运动障碍。我们假设 在选定的神经群体中激活 UPRmt 分支可以预防酒精性运动障碍。到 检验这一假设，我们提出两个具体目标：目标 1 将研究永久 UPRmt 如何防范 酒精介导的运动障碍；目标 2 将确定神经元 UPRmt 导致的机制 防止酒精介导的运动障碍。酒精介导的详细分析 在酒精介导的运动障碍的背景下，UPRmt 及其细胞内和细胞间信号传导将 导致有效的药物靶标，防止或改善酒精性运动障碍。