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: 8801326
• 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/8801326
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; American; Animal Model; Autophagocytosis; Autophagosome; Axon; Biological; Brain; 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; Laboratories; Life; 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; Staging; Synapses; Testing; Therapeutic; Time; Work; age related; aged; aging population; base; in vivo; insight; interdisciplinary approach; late endosome; mitochondrial autophagy; mitochondrial dysfunction; neuronal cell body; novel; parkin gene/protein; prevent; public health relevance; research study; 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）：阿尔茨海默氏病（AD）是一种与年龄相关的进行性神经退行性疾病，会影响衰老人口的惊人百分比，并导致记忆力丧失和认知能力下降。目前，有540万美国人患有广告，这是我们社会的主要健康问题。线粒体是供应ATP为神经元功能和生存至关重要的各种生物学活性提供动力的细胞能发电厂。活着的AD患者的成像研究显示，早期的线粒体缺陷 疾病阶段。线粒体功能障碍和氧化应激发生在AD动物模型中。线粒体有缺陷的积累是家族性和零星AD的特征，并且在AD病理生理学中起了早期的重要作用。已提出突触线粒体功能障碍是参与AD早期突触改变的关键因素。 Mitophagy是一种用于去除受损线粒体的货物特异性自噬溶质体途径，构成了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完整性和功能，从而阻止线粒体功能失调的线粒体积累。但是，一个长期存在的问题是，线粒体过程本身是否是通过AD启动机制的目标，以损害常规消除突触线粒体，从而为启动突触病理学做出重要贡献。我们最近揭示了Parkin介导的线粒体的独特特征，可以通过活成熟的皮质神经元中的自噬 - 溶酶体途径消除受损的线粒体。我们以前确定Snapin是一种动力蛋白运动适配器，通过协调晚期内体和内体 - 内体 - 雷症的逆行转运来上调溶酶体功能。我们最近的研究发现了AD神经元中的细胞途径改变：由于Snapin介导的和动力蛋白驱动的逆行转运的缺陷，底物蛋白水解受损。在当前的建议中，我们正在采用分子，细胞生物学的多学科方法，以及长时间的多频道实时成像中的成熟神经元中的多渠道实时成像，这些神经元与基因救援实验相结合的AD模型得出。通过这些方法，我们将阐明AD神经元中线粒体和溶酶体缺陷的基础机制，以及它们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AD模型中建立线粒体缺陷与线粒体病理学之间的病因联系；目的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小鼠大脑中线粒体病理和突触丧失的手术机制。预期确定的机制将为克服AD和其他与线粒体功能障碍和自噬 - 溶酶体病理学相关的新型保护和治疗策略的发展提供基础。