MITOCHONDRIAL DYSFUNCTION IN NEUROGEGENERATION OF AGING

描述（由申请人提供）：广泛、有力的证据表明，线粒体异常和氧化应激发生在阿尔茨海默病（AD）、亨廷顿病（HD）和其他神经退行性疾病中。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。本实验将阐明AD线粒体损伤的基本机制及其对脑损伤的影响。亨廷顿氏病（HD）也将被研究，因为它提供了机制上的见解。总的假设是：线粒体异常将基因缺陷和/或环境损害与神经退行性过程联系起来。这一提议测试了遗传变异（包括导致AD或HD的基因）和/或环境损害可能通过改变改变线粒体蛋白质和功能的蛋白质的活性或产生而产生线粒体功能障碍的可能性。由此产生的异常促进神经退行性变的机制将在生物复杂性的多个层面进行测试：基因转录、蛋白质、线粒体、完整的培养细胞、转基因小鼠和人类大脑。实验将集中在患病大脑中显著改变的两种酶系统：形成关键线粒体酶a-酮戊二酸脱氢酶复合物（KGDHC）和谷氨酰胺转酶（TGase）的蛋白质。AD和HD患者脑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。该项目将测试KGDHC减少的原因，以及减少对线粒体功能、细胞相互作用和神经变性的影响。我们的研究表明，在AD和HD的大脑和脑脊液中，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，并导致有助于诊断的TGase产物的积累。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，并有助于改善包括AD在内的与年龄相关的神经退行性疾病的新方法。

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.