MITOCHONDRIAL DYSFUNCTION IN NEURODENEGENERATION/AGING

氧化/能量代谢损伤是阿尔茨海默病（AD）的特征，也发生在CAGn/Qn扩张疾病中。在AD中，克雷布斯循环成分KGDHC缺乏。在本次修订的Program Project中，将阐明并比较AD和扩张障碍中能量/氧化代谢损伤的机制。项目1将阐明导致AD缺乏症的KGDHC组成蛋白的异常。自先前综述以来的新数据表明家族性AD亚群与KGDHC成分基因（DLST）多态性有关；这种明显的联系的基础也将被阐明。项目2将确定分离线粒体中KGDHC活性降低对氧化应激、钙代谢、通透性转变和mtDNA转录的影响。项目3的重点是确定已知导致神经变性的条件（如氧化应激、钙平衡）是否会损害完整培养细胞中的KGDHC，如果是这样，这种损害是否会导致细胞死亡或与神经变性相关的其他变化的发生。项目4将确定转谷氨酰胺酶（Tgase）介导的反应在CAGn/Qn疾病中的作用。由于上次审查以来的发现，本项目已进行了广泛修订。这些包括在体外证明，Tgase将Qn扩增与KGDHC和GAPDH共价连接。组蛋白上的酶作用聚集了它们。据报道，TGase活性在AD大脑中增加，并且被认为在AD和CAGn/Qn疾病的不溶性聚集体的形成中发挥作用。项目5是一个新项目。它将利用一些转基因小鼠模型来阐明AD和CAGn/Qn疾病的机制，包括一种新发现的KGDHC成分（Dld+/-）缺乏的小鼠杂合子。M. Flint Beal博士于1998年7月加入康奈尔大学（担任神经病学和神经科学系主任），将指导5号项目。行政核心将支持这些项目，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能量/氧化代谢异常在AD和CAGn/Qn疾病中的作用，包括KGDHC缺乏在AD的病理生理中是否重要。

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.