MITOCHONDRIAL DYSFUNCTION IN NEURODENEGENERATION/AGING

神经退行性疾病/衰老中的线粒体功能障碍

• 批准号: 6168993
• 负责人: JOHN P BLASS
• 金额: $ 112.62万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-02 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6168993
• 关键词: enzyme activity; mitochondria; neural degeneration; oxoglutarate dehydrogenase

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.

氧化/能量代谢受损是阿尔茨海默病 (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。在这个修订后的计划项目中，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 KGDHC 组成蛋白的异常，这些异常导致了 AD 中的 KGDHC 缺陷。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) 存在关联；这种明显关联的基础也将得到阐明。项目 2 将确定降低分离线粒体中 KGDHC 活性对氧化应激、钙代谢、通透性转变和 mtDNA 转录的影响 项目 3 重点确定已知导致神经变性的条件（例如氧化应激、钙平衡）是否会损害完整培养细胞中的 KGDHC，如果是，这种损害是否会导致细胞死亡或导致其他相关变化的发生 伴有神经退行性变。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，该项目已进行了广泛修改。其中包括证明在体外，Tgase 将 Qn 扩展与 KGDHC 以及 GAPDH 共价连接。 Tgase 对组蛋白的作用使它们聚集。据报道，TGase 活性在 AD 脑中增加，并且被认为在 AD 和 CAGn/Qn 疾病中不溶性聚集物的形成中发挥作用。项目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，包括新近获得的 KGDHC 成分缺陷杂合子小鼠 (Dld+/-)。 M. Flint Beal 博士于 1998 年 7 月加入康奈尔大学任教（担任神经病学和神经科学系主任），他将指导项目 5。行政核心将支持这些项目，组织培养核心将支持至少其中 3 个项目。项目之间的互动将非常密切。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。