MITOCHONDRIAL DYSFUNCTION IN NEUROGEGENERATION OF AGING

描述（由申请人提供）：大量有力的证据表明，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存在线粒体异常和氧化应激。最近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AD中线粒体损伤的基本机制以及它们如何导致脑损伤。亨廷顿氏病（HD）也将被研究，因为它提供了机制的见解。总体假设是：线粒体异常将基因缺陷和/或环境损伤与神经退行性过程联系起来。该提案测试了遗传变异（包括导致AD或HD的基因）和/或环境损伤可能通过改变蛋白质的活性或产生来产生线粒体功能障碍的可能性，所述蛋白质的活性或产生改变线粒体蛋白质和功能。由此产生的异常促进神经退行性变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酶系统，在患病的大脑显着改变：蛋白质，形成关键的线粒体酶α-酮戊二酸脱氢酶复合物（KGDHC）和转氨酶（TGase）。AD和HD患者的脑KGDHC活性下降。这种减少与临床状态高度相关，至少在AD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行性变的影响。我们的研究表明，AD和HD患者的脑和CSF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，并导致有助于诊断的TGase产物积累。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迟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行性过程提供新的见解，并有助于改善年龄相关神经退行性疾病（包括AD）的新方法。 主要研究者 博士加里吉布森是康奈尔大学韦尔医学院的神经病学教授。他是一位成熟的研究者，也是许多关于线粒体功能和神经退行性疾病之间关系的开创性研究的作者。他的研究生产力的记录是令人印象深刻的，他和他的小组非常适合进行拟议的研究。

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.