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局部脑部结构损伤和认知障碍。慢性 酒精滥用还与一系列运动障碍有关。慢性饮酒 单独或与酒精性肝性脑病一起，可引起各种类型的震颤、星状突起和 小脑功能障碍。虽然酒精引起的脑损伤是通过酒精对神经的影响来解释的 兴奋性或营养缺乏，我们还没有完全从分子和分子水平上了解其发病机制。 酒精产生毒性并损害神经系统的细胞水平。线虫线虫 是一种可用于剖析酒精中毒病理机制的可服从模式生物。 神经毒性。我们对线虫的研究表明，虽然酒精强烈地诱导了许多保守的细胞 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 长期酗酒。此外，一种特异地诱导神经元特异性UPRmt的基因操作 激活足以保护身体免受酒精引起的运动损伤。我们假设 在选定的神经群体中激活UPRmt的一个分支可以预防酒精运动障碍。至 检验这一假设，我们提出了两个具体目标：目标1将调查永久UPRmt如何预防 酒精介导的运动障碍；目标2将确定神经元UPRmt的领导机制 对酒精引起的运动损伤的保护。酒精介体的详细分析 UPRmt及其在酒精介导的运动障碍背景下的细胞内和细胞间信号转导将 导致有效的可用药靶点，防止或改善酒精运动障碍。