MITOCHONDRIAL DYSFUNCTION IN NEURODENEGENERATION/AGING

氧化/能量代谢的损伤是阿尔茨海默病（AD）的特征，并且也发生在CAGn/Qn扩展疾病中。在AD中，Krebs循环组分KGDHC缺乏。在这个修订后的计划项目中，能量/氧化代谢障碍的机制将被澄清和比较AD和扩张性疾病。项目1将阐明KGDHC组成蛋白的异常，这些蛋白是导致AD中KGDHC缺乏的原因。自上次审查以来的新数据表明，家族性AD的一个亚组与KGDHC成分的基因多态性（DLST）相关;这种明显相关性的基础也将得到阐明。项目2将确定在分离的线粒体中KGDHC活性降低对氧化应激、钙代谢、通透性转换和mtDNA转录的影响。项目3的重点是确定已知引起神经变性的条件是否（例如氧化应激、钙平衡）损害完整培养细胞中的KGDHC，如果是这样的话，这种损伤是否导致细胞死亡或与神经变性相关的其他变化的发展。项目4将确定转氨酶（TGase）介导的反应在CAGn/Qn疾病中的作用。由于上次审查以来的调查结果，对该项目进行了广泛修订。这些包括证明在体外，Tgase将Qn扩增共价连接到KGDHC以及GAPDH。TGase作用于组蛋白使其聚集。据报道，TG酶活性在AD脑中增加，并且已经提出在AD和CAGn/Qn病症中的不溶性聚集体的形成中起作用。5是一个新项目。它将利用许多转基因小鼠模型来阐明AD和CAGn/Qn疾病的机制，包括一种新的KGDHC（Dld+/-）组分缺乏的杂合子小鼠。M博士弗林特比尔，谁是加入康奈尔大学教师作为1998年7月（主席神经病学和神经科学），将直接项目5。一个行政核心将支持这些项目，一个组织培养核心将支持至少3个项目。项目之间的互动将是密切的。这些研究将进一步阐明AD和CAGn/Qn疾病中能量/氧化代谢异常的作用，包括KGDHC缺乏在AD的病理生理学中是否重要。

Impairments of oxidative/energy metabolism are characteristic of Alzheimer's Disease (AD) and also occur in CAGn/Qn expansion diseases. In AD, the Krebs cycle component KGDHC is deficient. In this revised Program Project, the mechanisms of the impairments of energy/oxidative metabolism will be clarified and compared in AD and in the expansion disorders. Project 1 will elucidate the abnormalities in the constituent proteins of KGDHC which are responsible for its deficiency in AD. New data since the previous review suggest an association of a subgroup of familial AD with polymorphisms in a gene (DLST) for a KGDHC constituent; the basis of this apparent association will also be elucidate. Project 2 will determine the effects of decreasing KGDHC activity in isolated mitochondria on oxidative stress, calcium metabolism, the permeability transition, and mtDNA transcription Project 3 focuses on determining whether conditions known to cause neurodegeneration (e.g. oxidative stress, calcium balance) impair KGDHC in intact, cultured cells, and if so whether such impairment contributes to cell death or to the development of other changes associated with neurodegeneration. Project 4 will determine the role of transglutaminase (Tgase)-mediated reactions in the CAGn/Qn diseases. This project has been extensively revised because of findings since the last review. These include demonstration that in vitro, Tgase covalently links Qn expansions to KGDHC as well as to GAPDH. Tgase action on histone aggregates them. TGase activity is reportedly increased in AD brain, and has been proposed to play a role in the formation of insoluble aggregates in both AD and CAGn/Qn disorders. Project 5 is a new project. It will utilize a number of transgenic mouse models to elucidate mechanisms in both AD and the CAGn/Qn disorders, including a newly available mouse heterozygous for deficiency of a component of KGDHC (Dld+/-). Dr. M. Flint Beal, who is joining the Cornell faculty as of July 1998 (as chair of Neurology and Neuroscience), will direct Project 5. An Administrative Core will support of the projects and a Tissue Culture Core will support at least 3 of the projects. Interactions among the Projects will be close. These studies will clarify further the role of abnormalities in energy/oxidative metabolism in AD and in the CAGn/Qn disorders, including whether or not the deficiency of KGDHC is important in the pathophysiology of AD.