Mitochondrial dysfunction and Alzheimer's disease

描述（由申请人提供）：最近发现的几种由哺乳动物核基因组编码的细菌脂肪酸合成途径酶的同源物，提出了哺乳动物细胞含有两种合成脂肪酸途径的可能性：线粒体细菌样途径和教科书细胞质途径。观察到该通路从细菌到哺乳动物高度保守，以及我们发现该通路的一个或多个组分的表达在线粒体疾病小鼠模型中受到差异调节，表明该通路在线粒体功能中起重要作用。这里提出的工作的第一个目的是首次表明哺乳动物线粒体能够通过这种途径制造脂肪酸。色谱技术将用于鉴定由线粒体脂肪酸合成（FASII）途径合成的产物和衍生物。siRNA介导的该通路的敲除将用于进一步阐明该通路在细胞中的功能。本提案的第二个具体目的是研究线粒体FASII途径在阿尔茨海默病中的作用。FASII通路的抑制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 -淀粉样蛋白的孵育和线粒体FASII产物的分析来研究。线粒体FASII通路与阿尔茨海默病之间关联的发现可能为阿尔茨海默病、帕金森病和其他神经退行性疾病的治疗提供见解和选择。

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.