MITOCHONDRIAL DYSFUNCTION IN NEURODENEGENERATION/AGING

氧化/能量代谢障碍是阿尔茨海默病(AD)的特征，也可见于CAGn/QN扩张性疾病。在AD中，Krebs旋回分量KGDHC缺乏。在这个修订的计划项目中，将阐明和比较AD和扩张性疾病中能量/氧化代谢损伤的机制。项目1将阐明KGDHC组成蛋白的异常，这些异常是导致其在AD中缺乏的原因。自前次综述以来的新数据表明，家族性AD的一个亚组与KGDHC成分的一个基因(DLST)的多态有关；这种明显的相关性的基础也将被阐明。项目2将确定KGDHC活性降低对氧化应激、钙代谢、通透性转变的影响，以及mtDNA转录项目3的重点是确定已知的导致神经退化的条件(例如，氧化应激、钙平衡)是否损害完整的培养细胞中的KGDHC，如果是，这种损害是否有助于细胞死亡或与神经退化相关的其他变化的发展。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。自上次审查以来，由于调查结果，该项目已作了广泛的修订。这些包括证明在体外，Tgase将QN的扩展与KGDHC以及GAPDH共价连接。组蛋白上的Tgase作用使它们聚集在一起。据报道，TGase活性在AD脑中增加，并被认为在AD和CAGn/QN疾病中都在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，包括新获得的KGDHC一个成分缺乏的杂合子小鼠(DLD+/-)。M.Flint Beal博士将于1998年7月加入康奈尔大学教职员工(担任神经学和神经科学主席)，他将指导项目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三个项目。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紊乱中的作用，包括KGDHC缺陷是否在AD的病理生理学中起重要作用。

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.