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结构损伤和认知障碍。慢性