Mitochondrial dysfunction and Alzheimer's disease

线粒体功能障碍和阿尔茨海默病

• 批准号: 7343220
• 负责人: DEBORAH G MURDOCK
• 金额: $ 15.98万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7343220
• 关键词: Acids; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Amyloid; Apoptosis; Bacteria; Brain; Cardiolipins; Cells; Enzymes; Fatty Acids; Functional disorder; Genome; Homologous Gene; Human; Inherited; Knock-out; Life; Mammalian Cell; Mammals; Mediating; Mediator of activation protein; Mitochondria; Mitochondrial Diseases; Modeling; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Oxidative Stress; Parkinson Disease; Pathway interactions; Patients; Phenotype; Phospholipids; Play; Protein Overexpression; Proteins; Research; Research Personnel; Role; Small Interfering RNA; Techniques; Textbooks; Thioctic Acid; Time; Work; cytochrome c oxidase; enzyme activity; enzyme pathway; hydroxyacyl-Coenzyme A dehydrogenase, type II, human; insight; ketoglutarate dehydrogenase; knock-down; member; mitochondrial dysfunction; mouse model; neurotoxicity; pyruvate dehydrogenase; respiratory

DESCRIPTION (provided by applicant): The recent finding of several homologues of the bacterial fatty acid synthesis pathway enzymes encoded by the mammalian nuclear genome has raised the possibility that mammalian cells contain two pathways to synthesize fatty acids: a mitochondrial bacteria-like pathway, and the textbook cytoplasmic pathway. The observation that this pathway is highly conserved from bacteria to mammals, and our finding that the expression of one or more components of the pathway is differentially regulated in a mouse model of mitochondrial disease, suggests that this pathway plays an important role in mitochondrial function. The first aim of the work proposed here is to show for the first time that mammalian mitochondria are capable of making fatty acids via this pathway. Chromatographic techniques will be used to identify the products and derivatives that are synthesized by the mitochondrial fatty acid synthesis (FASII) pathway. siRNA mediated knock-down of the pathway will be used to further elucidate the function of this pathway in the cell. The second specific aim of this proposal is to investigate the role of the mitochondrial FASII pathway in Alzheimer's disease. The proposed phenotypes that would be expected from inhibition of the FASII pathway resemble the mitochondrial dysfunction seen in the brain of patients with Alzheimer's disease. The possibility that B-amyloid causes mitochondrial dysfunction through inhibition of the fatty acid synthesis pathway will be investigated through incubation of mitochondria with B-amyloid, and analysis of the products of mitochondrial FASII. The discovery of an association between the mitochondrial FASII pathway and Alzheimer's disease may provide insight into and treatment options for Alzheimer's, Parkinson's, and other neurodegenerative disorders.

描述(申请人提供)：最近由哺乳动物核基因组编码的细菌脂肪酸合成途径酶的几个同源物的发现增加了哺乳动物细胞含有两条合成脂肪酸的途径的可能性：线粒体细菌样途径和教科书上的细胞质途径。这一途径从细菌到哺乳动物高度保守的观察结果，以及我们在线粒体疾病小鼠模型中发现该途径的一个或多个组成部分的表达受到差异调控的发现，表明该途径在线粒体功能中发挥着重要作用。这里提出的这项工作的第一个目的是首次证明哺乳动物线粒体能够通过这一途径制造脂肪酸。将使用色谱技术来鉴定通过线粒体脂肪酸合成(FASII)途径合成的产品和衍生物。SiRNA介导的该途径的敲除将被用来进一步阐明该途径在细胞中的功能。这项建议的第二个具体目标是调查线粒体FASII途径在阿尔茨海默病中的作用。抑制FASII通路所提出的表型类似于阿尔茨海默病患者大脑中的线粒体功能障碍。B-淀粉样蛋白通过抑制脂肪酸合成途径导致线粒体功能障碍的可能性将通过线粒体与B-淀粉样蛋白的孵育以及对线粒体FASII产物的分析来研究。线粒体FASII通路与阿尔茨海默病之间的关联的发现可能为阿尔茨海默氏症、帕金森氏症和其他神经退行性疾病提供洞察和治疗选择。