Regulation of Mitochondrial Quality Through Mitophagy in Alzheimer's Disease

阿尔茨海默病中通过线粒体自噬调节线粒体质量

• 批准号: 9308029
• 负责人: Qian Cai
• 金额: $ 33.91万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308029
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; American; Animal Model; Autophagocytosis; Autophagosome; Axon; Biological; Brain; Brain Diseases; Cell physiology; Cellular biology; Cognitive deficits; Defect; Development; Disease; Disease Progression; Disease model; Dynein ATPase; Employee Strikes; Ensure; Excision; Functional disorder; Genes; Goals; Health; Human; Image; Impaired cognition; Impairment; Laboratories; Link; Lysosomes; Mediating; Memory Loss; Mitochondria; Molecular; Motor; Mus; Neurodegenerative Disorders; Neurons; Oxidative Stress; PINK1 gene; Pathology; Pathway interactions; Patients; Physiological; Play; Positioning Attribute; Power Plants; Preventive; Process; Proteolysis; Publishing; Quality Control; Regulation; Research; Role; SNAPIN gene; Societies; Synapses; Testing; Therapeutic; Time; Work; age related; aged; aging population; experimental study; imaging study; in vivo; insight; interdisciplinary approach; late endosome; mitochondrial autophagy; mitochondrial dysfunction; neuronal cell body; novel; parkin gene/protein; prevent; public health relevance; retrograde transport; trafficking

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease that affects a staggering percentage of the aging population and causes memory loss and cognitive decline. Currently, 5.4 million Americans suffer from AD, which is a major health concern in our society. Mitochondria are cellular energy power plants that supply ATP to power various biological activities essential for neuronal function and survival. Imaging studies in living AD patients reveal mitochondrial deficits at early disease stage. Mitochondrial dysfunction and oxidative stress occur early in animal models of AD. Accumulation of defective mitochondria is a feature of both familial and sporadic AD and plays an early important role in AD pathophysiology. Dysfunction of synaptic mitochondria has been proposed as a key factor involved in early synaptic alterations in AD. Mitophagy, a cargo-specific autophagy-lysosomal pathway for removal of damaged mitochondria, constitutes a key cellular pathway in mitochondrial quality control. Recent studies indicate that PINK1/Parkin- mediated pathways ensure mitochondrial integrity and function, thus preventing from the accumulation of dysfunctional mitochondria. However, a long-standing question is whether the mitophagy process itself is targeted by AD initiation mechanisms to impair routine elimination of synaptic mitochondria, and thereby make critical contributions to initiating synaptic pathology. We recently revealed unique features of Parkin-mediated mitophagy to eliminate damaged mitochondria via the autophagy-lysosomal pathway in live mature cortical neurons. We previously established that Snapin, a dynein motor adaptor, up-regulates lysosomal function by coordinating retrograde transport of late endosomes and late endosome-lysosomal trafficking in neurons. Our recent study uncovered an altered cellular pathway in AD neurons: an impaired substrate proteolysis due to the defects in Snapin-mediated and dynein-driven retrograde transport. In the current proposal, we are applying multidisciplinary approaches of molecular, cell biology, and long time-lapse with multi-channel live imaging in mature neurons derived from an AD model combined with gene rescue experiments. With these approaches, we will elucidate the mechanisms underlying mitophagy and lysosomal deficits in AD neurons, and their impact on quality control of axonal mitochondria. This is a key dynamic cellular process directly linked to early pathophysiology of AD. Three specific aims are proposed: Aim 1 is to establish a causative linkage between mitophagy deficit and mitochondrial pathology in a physiological AD model; Aim 2 is to determine whether lysosomal deficits constitute a core aspect of mitochondrial quality control deficiency in AD neurons; and Aim 3 is to elucidate operative mechanisms rescuing mitochondrial pathology and synapse loss in AD mouse brains. The identified mechanisms are expected to provide the basis for the development of novel protective and therapeutic strategies to overcome AD and other major neurodegenerative diseases associated with mitochondrial dysfunction and autophagy-lysosomal pathology.

描述（由申请人提供）：阿尔茨海默病（AD）是一种与年龄相关的进行性神经退行性疾病，影响着惊人比例的老龄化人口，并导致记忆丧失和认知能力下降。目前，有 540 万美国人患有 AD，这是我们社会的一个主要健康问题。线粒体是细胞能量发电厂，提供 ATP 来为神经元功能和生存所必需的各种生物活动提供动力。对活体 AD 患者的影像学研究揭示了早期线粒体缺陷 疾病阶段。线粒体功能障碍和氧化应激在 AD 动物模型中早期发生。有缺陷的线粒体的积累是家族性和散发性 AD 的一个特征，并且在 AD 病理生理学中发挥着早期重要作用。突触线粒体功能障碍被认为是 AD 早期突触改变的关键因素。线粒体自噬是一种用于去除受损线粒体的货物特异性自噬溶酶体途径，是线粒体质量控制中的关键细胞途径。最近的研究表明，PINK1/Parkin 介导的途径可确保线粒体的完整性和功能，从而防止功能失调的线粒体积累。然而，一个长期存在的问题是线粒体自噬过程本身是否是 AD 启动机制的目标，以损害突触线粒体的常规消除，从而对启动突触病理学做出关键贡献。我们最近揭示了 Parkin 介导的线粒体自噬的独特特征，可通过活成熟皮层神经元中的自噬-溶酶体途径消除受损的线粒体。我们之前确定，Snapin（一种动力蛋白运动适配器）通过协调神经元中晚期内体的逆行运输和晚期内体-溶酶体运输来上调溶酶体功能。我们最近的研究发现 AD 神经元中细胞通路发生了改变：由于 Snapin 介导和动力蛋白驱动的逆行运输缺陷，底物蛋白水解受损。在当前的提案中，我们正在应用分子、细胞生物学和长延时多通道实时成像的多学科方法，对源自 AD 模型的成熟神经元进行多通道实时成像，并结合基因拯救实验。通过这些方法，我们将阐明 AD 神经元线粒体自噬和溶酶体缺陷的机制，及其对轴突线粒体质量控制的影响。这是与 AD 早期病理生理学直接相关的关键动态细胞过程。提出了三个具体目标： 目标 1 是在生理性 AD 模型中建立线粒体自噬缺陷和线粒体病理学之间的因果关系；目标 2 是确定溶酶体缺陷是否构成 AD 神经元线粒体质量控制缺陷的核心方面；目标 3 是阐明挽救 AD 小鼠大脑线粒体病理和突触损失的操作机制。所确定的机制有望为开发新的保护和治疗策略提供基础，以克服 AD 和与线粒体功能障碍和自噬溶酶体病理学相关的其他主要神经退行性疾病。