Role of mitochondrial GDAP1 in Alzheimer's disease

线粒体 GDAP1 在阿尔茨海默病中的作用

• 批准号: 10739858
• 负责人: KIRILL KISELYOV
• 金额: $ 67.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739858
• 关键词: 4 hydroxynonenal; Address; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amino Acids; Amyloid beta-Protein Precursor; Antioxidants; Automobile Driving; Autopsy; Binding; Brain; Brain region; Calcium; Calcium Signaling; Cell model; Cells; Charcot-Marie-Tooth Disease; Communication; Complex; Cytoprotection; Data; Data Set; Defect; Disease; Disease Progression; Drug Metabolic Detoxication; Enzymes; Epigenetic Process; Equilibrium; Etiology; Excision; Fibroblasts; GDAP protein; Gene Proteins; Genes; Genetic; Glutathione; Glutathione S-Transferase; HDAC1 gene; Homeostasis; Human; Knowledge; Ligands; Lipid Peroxidation; Lipids; Maintenance; Maps; Measures; Mediating; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Molecular Target; Morphology; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organelles; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Peripheral Nervous System Diseases; Physiology; Prefrontal Cortex; Protein Isoforms; Proteins; Proteomics; Regulation; Reporting; Research; Role; Sampling; Site; Skin; Testing; Therapeutic Intervention; Time; Translating; VDAC1 gene; Xenobiotics; abeta accumulation; adduct; cell motility; drug candidate; human disease; longitudinal positron emission tomography; member; mouse model; mutant; neuropathology; overexpression; oxidative damage; response; tau Proteins; tau aggregation; tau dysfunction; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Despite extensive research, we still do not fully understand how neurons die in Alzheimer’s disease (AD) patients' brains after withstanding decades of the accumulation of AD pathology. Oxidative damage and mitochondrial deficits are proposed to contribute to or drive neurodegeneration in AD. AD brains show an accumulation of the toxic end-product of lipid peroxidation 4-hydroxynoneal (4HNE), but it remains unclear what causes 4HNE to accumulate in AD. Moreover, a mechanistic understanding of the increased sensitivity of mitochondria and neurons in AD to oxidative damage is lacking. We determined that an atypical member of the glutathione S- transferase (GST) superfamily, GDAP1 (Ganglioside Induced Differentiation Associated Protein 1), binds 4HNE through a unique sequence motif called the α-loop, which is also essential for GDAP1 function. These data collectively indicate that 4HNE is a GDAP1 substrate and that 4HNE binding to GDAP1 is essential for the maintenance of cellular redox balance and mitochondrial function. Significantly, our preliminary RNAseq data from AD patients and analysis of four AD proteomic datasets show significantly reduced levels of GDAP1 in the prefrontal cortex of AD patients. As such, we hypothesize that GDAP1 protects mitochondria against oxidative damage by neutralizing the highly toxic 4HNE and that reduced levels of GDAP1 render AD patient brains vulnerable to 4HNE-mediated damage. We will test this hypothesis with two Aims. Aim 1 will determine the mechanism of GDAP1-mediated cryoprotection including the mechanisms of 4HNE binding and detoxification. Aim 2 will determine the impact of reduced levels of GDAP1 on mitochondrial function and accumulation of the pathological hallmarks of AD in directly converted induced neurons from control subjects and AD patients. These studies will establish the relationship between reduced GDAP1 levels, elevated 4HNE levels, and the increased vulnerability of neurons in AD patients to oxidative damage and open a potential avenue for therapeutic intervention in AD.

项目摘要 尽管进行了广泛的研究，但我们仍然不完全了解神经元如何在阿尔茨海默氏病（AD）患者中死亡。 大脑经过数十年的AD病理积累。氧化损伤和线粒体 提出缺陷为AD中的神经退行性造成贡献。广告大脑显示了 脂质过氧化4-羟基诺尼（4HNE）的有毒终产物，但仍不清楚是什么原因导致4HNE 积聚在AD中。此外，对线粒体和线粒体敏感性提高的机械理解 缺乏对氧化损伤的AD中的神经元。我们确定了谷胱甘肽的非典型成员 转移酶（GST）超家族GDAP1（神经节诱导的分化蛋白1）结合4HNE 通过称为α-环的唯一序列基序，这对于GDAP1函数也是必不可少的。这些数据 共同表示4HNE是GDAP1底物，而4HNE与GDAP1的结合对于 维持细胞氧化还原平衡和线粒体功能。值得注意的是，我们的初步RNASEQ数据 从AD患者和四个AD蛋白质组学数据集的分析显示，GDAP1的水平显着降低 AD患者的前额叶皮层。因此，我们假设GDAP1可保护线粒体免受氧化的影响 通过中和剧毒4HNE的损害，并降低GDAP1的水平使AD患者大脑 容易受到4HNE介导的损伤。我们将以两个目标检验这一假设。 AIM 1将确定 GDAP1介导的冷冻保护机制，包括4HNE结合和排毒的机制。 AIM 2将确定降低GDAP1水平对线粒体功能和积累的影响 直接转化为对照组和AD患者的直接转化诱导神经元的AD的病理标志。这些 研究将确定降低的GDAP1水平，4HNE水平升高和增加之间的关系 AD患者神经元的脆弱性可氧化损伤并打开潜在的治疗途径 干预广告。