Tau causes neurodegeneration in vivo through mitochondrial disruption

Tau 通过线粒体破坏引起体内神经变性

• 批准号: 7680598
• 负责人: Brian Michael DuBoff
• 金额: $ 3.23万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680598
• 关键词: Acetyltransferase; Actins; Address; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Biochemical Pathway; Biological Models; Cessation of life; Charcot-Marie-Tooth Disease; Clinical; Complement; Complex; Cytoskeleton; Data; Defect; Dependence; Disease; Disease model; Drosophila genus; Drosophila melanogaster; Electron Transport; Energy Metabolism; Event; F-Actin; Frequencies; Gene Mutation; Genetic; Health; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Huntington Disease; Impaired cognition; Laboratories; Longevity; Mediating; Memory Loss; Mitochondria; Modeling; Morphology; Mutation; NADH dehydrogenase (ubiquinone); Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organelles; Parkinson Disease; Pathogenesis; Pathology; Patients; Phenotype; Play; Primary Cell Cultures; Proteins; Reactive Oxygen Species; Reporting; Research; Role; Source; Therapeutic Effect; Tissues; Toxic effect; Transgenic Animals; Work; fly; fusion gene; human disease; in vivo; mitochondrial dysfunction; mouse model; neuron loss; neurotoxicity; parkin gene/protein; polyglutamine; protein misfolding; research study; tau Proteins; tau expression

DESCRIPTION (provided by applicant): Alzheimer's disease is a devastating neurodegenerative disorder that affects an estimated 20 million people worldwide. The disease causes progressive memory loss, cognitive decline, and ultimately death. In recent years multiple genetic mutations have been identified that can give rise to the disease, but to date the pathogenic mechanisms remain elusive. Mitochondria are an attractive candidate for analyzing Alzheimer's disease pathogenesis, as mitochondria are the primary sources of ATP and reactive oxygen species, both of which must be closely controlled to maintain neuronal health. Examination of post-mortemAlzheimer's disease tissue reveals defects in mitochondrial morphology and increased mitochondrial DMA mutation, raising the possibility that mitochondria are contributing causally to Alzheimer's disease. Mitochondria are dynamic organelles that undergo continual fission and fusion events, which are essential for mitochondrial function and intracellular distribution. Disruption of mitochondrial fusion has been implicated in multiple neurodegenerative diseases, including Charcot-Marie-Tooth disease. Actin stabilization, which is increased by tau expression, has also been demonstrated to both alter mitochondrial function and promote mitochondrial fission. It remains to be determined whether mitochondrial fission and fusion are altered in Alzheimer's disease. An excellent model system to address this question is the fruit fly Drosophila melanogaster. Alzheimer's disease is modeled in Drosophila by expression of the human disease- associated protein tau. Preliminary data in this model suggests that tau expression alters mitochondrial morphology, distribution, and function. There is also evidence that altering mitochondrial fissionreverses multiple tau-induced mitochondrial defects. It remains to be determined whether manipulating mitochondrial fission and fusion can suppress tau-induced toxicity in this model. To address this question, mitochondrial fission and fusion genes will be manipulated in adult flies and in primary cell culture to examine the effects on tau-mediated mitochondrial phenotypes and toxicity. Additionally, actin stabilization will be modulated to determine an effect on tau-induced mitochondrial abnormalities, including altered fission and fusion. Alzheimer's disease is a devastating neurodegenerative disorder that affects 20 million people worldwide, and the underlying causes of the disease remain unclear. Mitochondrial defects have been implicated in the pathogenesis of multiple neurodegenerative diseases. Post-mortem tissue analysis suggests mitochondria may be involved in Alzheimer's disease, making mitochondria a strong candidate for disease research.

描述（由申请人提供）：阿尔茨海默病是一种毁灭性的神经退行性疾病，影响全球约2000万人。这种疾病会导致渐进性记忆丧失，认知能力下降，最终死亡。近年来，已经确定了多种基因突变可以引起疾病，但迄今为止，致病机制仍然难以捉摸。线粒体是分析阿尔茨海默病发病机制的有吸引力的候选者，因为线粒体是ATP和活性氧的主要来源，这两者都必须被密切控制以维持神经元的健康。对死后阿尔茨海默病组织的检查揭示了线粒体形态的缺陷和线粒体DNA突变的增加，这提高了线粒体与阿尔茨海默病有因果关系的可能性。线粒体是一种动态的细胞器，它经历不断的分裂和融合事件，这是线粒体功能和细胞内分布所必需的。线粒体融合的破坏与多种神经退行性疾病有关，包括腓骨肌萎缩症。肌动蛋白稳定化（通过tau表达而增加）也已被证明可以改变线粒体功能并促进线粒体分裂。线粒体分裂和融合是否在阿尔茨海默病中改变仍有待确定。解决这个问题的一个很好的模型系统是果蝇Drosophila melanogaster。阿尔茨海默病在果蝇中通过表达人类疾病相关蛋白tau来建模。该模型的初步数据表明，tau蛋白的表达改变了线粒体的形态、分布和功能。也有证据表明，改变线粒体分裂逆转多个tau诱导的线粒体缺陷。在该模型中，操纵线粒体分裂和融合是否可以抑制tau诱导的毒性仍有待确定。为了解决这个问题，将在成年果蝇和原代细胞培养中操纵线粒体分裂和融合基因，以检查对tau介导的线粒体表型和毒性的影响。此外，将调节肌动蛋白稳定化以确定对tau诱导的线粒体异常的影响，包括改变的分裂和融合。阿尔茨海默病是一种毁灭性的神经退行性疾病，影响全球2000万人，该疾病的根本原因仍不清楚。线粒体缺陷与多种神经退行性疾病的发病机制有关。死后组织分析表明线粒体可能与阿尔茨海默病有关，这使得线粒体成为疾病研究的有力候选者。