Mitochondrial and Metabolic Dysfunction in Age-related Neurodegeneration

 描述(申请人提供)：包括阿尔茨海默病(AD)在内的与年龄相关的神经退行性疾病与轻度氧化代谢障碍、氧化应激和异常蛋白质积累有关。糖代谢降低和线粒体功能异常是AD的不变特征。这些变化发生在疾病的早期，可以可信地与包括斑块、缠绕和记忆障碍在内的病理联系起来。我们之前的研究证实了我们的基本假设，即年龄相关神经退行性疾病中的线粒体功能障碍促进了疾病的发展，并损害了大脑的适应能力。当前的计划项目将测试这些变化的基本机制，并测试扭转赤字的多种方法。这一建议的基本假设是，能量代谢关键蛋白以及可塑性基因的翻译后修饰和转录在AD患者中异常，并形成有效的治疗靶点。对代谢状态敏感的蛋白质修饰，包括乙酰化、甲基化和琥珀酸化，可能会改变线粒体中的蛋白质相互作用以及蛋白质调节转录的能力。刺激生物发生的基因PGC-1α、NRF2/ARE的激活及其与选择性sirtuins(NAD依赖的脱乙酰酶)的关系将在AD小鼠模型以及来自人类和啮齿动物的培养细胞中进行测试。线粒体与细胞核和胞浆的相互作用可能促进分裂、融合、有丝分裂或自噬，并改变TCA循环基因的转录。调节线粒体蛋白质组组成的蛋白质表达的变化可能会影响能量代谢和线粒体对氧化应激的贡献。可塑性基因及其乙酰化和甲基化对转录的修饰直接与代谢相关 转录和可塑性。可塑性相关基因表达的可逆性抑制和学习记忆能力的下降为AD相关改变及其逆转提供了机制。这些项目的目标的成功完成有望为神经退化过程提供新的见解，并有助于采用新的方法来改善与年龄相关的神经退化。

 DESCRIPTION (provided by applicant): Age-related neurodegenerative diseases including Alzheimer's Disease (AD) are associated with mild impairment of oxidative metabolism, oxidative stress and accumulation of abnormal proteins. Diminished glucose metabolism and abnormal mitochondrial function are invariant features of AD. The changes occur early in the disease and can be plausibly linked to the pathology including the plaques, tangles and memory deficits. Our previous studies proved our underlying hypothesis that "mitochondrial dysfunction in age-related neurodegenerative diseases promotes the development of disease and impairs the ability of the brain to adapt". The current program project will test the underlying mechanism for those changes, and test multiple approaches for reversing the deficits. The underlying hypothesis for this proposal is that posttranslational modifications and transcription for key proteins of energy metabolism as well as plasticity genes are abnormal in AD and form effective therapeutic targets. Protein modifications that are sensitive to metabolic state including acetylation, methylation and succinylation may alter protein interactions in the mitochondria as well as the ability of proteins to modulate transcription. Activation of genes PGC-1alpha, NRF2/ARE that stimulate biogenesis and the relationship to selective sirtuins (NAD-dependent deacetylases) will be tested in mouse models of AD as well as cultured cells from humans and rodents. The cross talk of mitochondria with the nucleus and cytosol may promote fission, fusion, mitophagy or autophagy and alter transcription of TCA cycle genes. Changes in the expression of the proteins modulating the mitochondrial proteome composition may affect the energy metabolism and the contribution of mitochondria to oxidative stress. The plasticity genes and the modification of their transcription by acetylation and methylation directly link metabolism and transcription and plasticity. The reversible repression of plasticity associated gene expression and diminished learning and memory provide a mechanism for AD related changes and their reversal. 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 neurodegeneration.