MITOCHONDRIAL DYSFUNCTION IN NEUROGEGENERATION OF AGING

描述(由申请人提供)：广泛而有力的证据表明，线粒体异常和氧化应激在阿尔茨海默病(AD)以及亨廷顿病(HD)和其他神经退行性疾病中发生。最近来自几个实验室的研究将线粒体损伤与AD淀粉样蛋白联系起来。拟议的实验将阐明阿尔茨海默病线粒体损伤的基本机制，以及它们如何导致脑损伤。亨廷顿病(HD)也将被研究，因为它提供了机械性的见解。总体假设是：线粒体异常将基因缺陷和/或环境侮辱与神经退化过程联系起来。这项提议测试了遗传变异(包括导致AD或HD的基因)和/或环境侮辱可能通过改变其作用改变线粒体蛋白质和功能的蛋白质的活动或产生而导致线粒体功能障碍的可能性。由此产生的异常促进神经退化的机制将在多个生物复杂性水平上进行测试：基因转录、蛋白质、线粒体、完整的培养细胞、转基因小鼠和人脑。这些实验将集中在两个在疾病大脑中发生显著变化的酶系统：形成关键线粒体酶a-酮戊二酸脱氢酶复合体(KGDHC)的蛋白质和转谷氨酰胺酶(TGase)。AD和HD患者脑组织KGDHC活性下降。这种减少与临床状态高度相关，至少在阿尔茨海默病中是这样。该计划项目将测试为什么KGDHC减少，以及减少对线粒体功能、细胞相互作用和神经退化的影响。我们的研究表明，AD和HD患者大脑和脑脊液中TGase产物显著增加。拟议的实验将测试TGase活性的变化是否会改变转录机制，使包括KGDHC在内的线粒体酶失活，并导致TGase产物的积累，从而有助于诊断。我们将确定改进的TGase抑制剂，并测试它们和/或促进线粒体功能的药物是否会延缓AD和HD转基因小鼠模型的病理和病理生理变化。这些项目目标的成功完成有望为神经退化过程提供新的见解，并有助于改善包括阿尔茨海默病在内的与年龄相关的神经退化的新方法。 首席调查员 加里·吉布森博士是康奈尔大学韦尔医学院的神经学教授。他是一位享有盛誉的研究人员，也是许多关于线粒体功能和神经变性之间关系的开创性研究的作者。他的研究效率记录令人印象深刻，他和他的团队非常适合开展拟议的研究。

DESCRIPTION (provided by applicant): Extensive, robust evidence indicates that mitochondrial abnormalities and oxidative stress occur in Alzheimer's disease (AD) as well as in Huntington's disease (HD) and other neurodegenerative disorders. Recent studies from several laboratories link mitochondrial damage to AD amyloid. The proposed experiments will elucidate the fundamental mechanisms of mitochondrial damage in AD and how they contribute to brain damage. Huntington's disease (HD) will also be studied because of the mechanistic insights it offers. The overall hypothesis is: mitochondrial abnormalities link gene defects and/or environmental insults to the neurodegenerative process. This proposal tests the possibility that genetic variation (including genes that cause AD or HD) and/or environmental insults may produce mitochondrial dysfunction by altering the activities or production of proteins whose actions modify mitochondria proteins and function. The mechanism by which the resulting abnormalities promote neurodegeneration will be tested at multiple levels of biological complexity: gene transcription, proteins, mitochondria, intact cultured cells, transgenic mice and human brains. The experiments will focus on two enzyme systems that are markedly altered in diseased brains: the proteins that form the key mitochondrial enzyme a-ketoglutarate dehydrogenase complex (KGDHC) and transglutaminase (TGase). Brain KGDHC activity declines in AD and HD. The reduction correlates highly with clinical state, at least in AD. The Program Project will test why KGDHC is decreased and the implications of the reduction for mitochondrial function, for cellular interactions and for neurodegeneration. Our studies have shown marked increases in TGase products in AD and HD in both brain and CSF. The proposed experiments will test whether changes in TGase activity alters transcriptional mechanisms, inactivates mitochondrial enzymes including KGDHC, and causes accumulation of TGase products that can aid diagnosis. We will identify improved TGase inhibitors and test whether they and/or agents that promote mitochondrial function will delay pathological and pathophysiological changes in transgenic mouse models of AD and HD. Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations including AD. PRINCIPAL INVESTIGATOR Dr. Gary Gibson is a Professor of Neurology at the Weil Medical School of Cornell University. He is an established investigator and an author of many pioneering studies on the relationship between mitochondrial function and neurodegeneration. His record of research productivity is impressive and he and his group are well suited to carry out the proposed research.