Project 5: Unraveling mechanisms for neurological diseases caused by ATAD3A mutations

项目5：揭示ATAD3A突变引起的神经系统疾病的机制

• 批准号: 10225578
• 负责人: Wan Hee Yoon
• 金额: $ 39.38万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225578
• 关键词: ATP phosphohydrolase; Acids; Affect; Biogenesis; Biology; Cardiolipins; Cardiomyopathies; Cells; Cholesterol; Cholesterol Homeostasis; Complex; DNA biosynthesis; Defect; Developmental Biology; Disease; Drosophila genus; Ethanolamines; Excretory function; Exhibits; Family; Genetic; Genetic Diseases; Goals; Hereditary Spastic Paraplegia; Homeostasis; Knowledge; Link; Maintenance; Membrane; Membrane Lipids; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mitochondrial Proteins; Molecular; Molecular Chaperones; Muscle; Mutate; Mutation; Neurodegenerative Disorders; Neurologic; Neurons; OPA1 gene; Oklahoma; Optic Atrophy; Pathogenicity; Pathologic; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phospholipids; Play; Pontocerebellar hypoplasia; Prevention; Proteins; Role; Secondary to; Site; Syndrome; Testing; Therapeutic; Variant; base; brain malformation; fly; heart function; induced pluripotent stem cell; insight; lipid metabolism; loss of function; mitochondrial dysfunction; mitochondrial membrane; mutant; nervous system disorder; new therapeutic target; prevent; respiratory; therapeutic target

PROJECT SUMMARY/ABSTRACT Mitochondrial dysfunction is a pathological feature of many neurodegenerative diseases. We recently discovered that mutations in the mitochondrial protein ATAD3A (ATPase family, AAA domain containing 3A) cause HAREL- YOON syndrome, a disease characterized by peripheral neuropathy, optic atrophy, cardiomyopathy, and brain malformation. ATAD3A is implicated in other neurological genetic diseases, including hereditary spastic paraplegia, and congenital pontocerebellar hypoplasia, with abnormal cholesterol metabolism suggested as an underlying cause. Although ATAD3A is known to influence mitochondrial biology and lipid metabolism, how mutations in ATAD3A cause disease is unknown. There is an urgent need to fill this knowledge gap in order to prevent or treat ATAD3A-associated and other mitochondrial diseases, most of which have no known cure. Our long-term goal is to discover new therapeutic targets and strategies for mitochondrial diseases. The objective of our proposal is to uncover the mechanisms by which ATAD3A controls mitochondrial functions, using Drosophila and ATAD3A patient-derived induced pluripotent stem cells. Our CENTRAL HYPOTHESIS is that ATAD3A regulates mitochondrial membrane lipid homeostasis, and thus mitochondrial membrane dynamics, mitochondrial DNA (mtDNA) replication, and lipid metabolism, based on the following compelling evidence. First, ATAD3A plays a role in the formation of ER-mitochondria contact sites (EMCS) which are essential for import and synthesis of phospholipids. Second, ATAD3A is essential for importing cholesterol into mitochondria as well as maintaining cholesterol-rich mitochondria membrane structures. Lastly, patients carrying ATAD3A mutations exhibit increased 3-methylglutaconic acid excretion, which is often caused by a deficiency in mitochondrial respiratory complexes secondary to defects in cardiolipin remodeling. We expect that mechanistic insight into the consequences of ATADA3 mutations derived from our studies will reveal unanticipated therapeutic targets for prevention or treatment of a variety of mitochondrial diseases. We will test our central hypothesis by performing the following Specific Aims: (1) Elucidate how ATAD3A regulates mitochondrial membrane dynamics; (2) Determine how ATAD3A promotes mtDNA replication in neurons; and (3) Determine how ATAD3A regulates proper heart function. Upon conclusion of our studies, we expect to uncover how ATAD3A modulates mitochondria membrane dynamics, biogenesis, and heart function. Understanding how ATAD3A links diverse aspects of mitochondrial biology is expected to have a positive impact by revealing the molecular basis, as well as novel therapeutic targets and strategies for ATAD3A-associated diseases and other disorders caused by mitochondrial dysfunction.

项目摘要/摘要 线粒体功能障碍是许多神经退行性疾病的病理特征。我们最近发现 线粒体蛋白ATAD3A(ATPase家族，包含3A的AAA结构域)的突变导致Harel- Yoon综合征，一种以周围神经病变、视神经萎缩、心肌病和脑为特征的疾病 畸形。ATAD3A与其他神经遗传性疾病有关，包括遗传性痉挛 截瘫和先天性桥小脑发育不良，胆固醇代谢异常提示为 根本原因。虽然已知ATAD3A影响线粒体生物学和脂质代谢，但如何 ATAD3A基因突变导致疾病的原因尚不清楚。迫切需要填补这一知识空白，以便 预防或治疗ATAD3A相关的疾病和其他线粒体疾病，其中大多数尚不能治愈。 我们的长期目标是发现线粒体疾病的新治疗靶点和策略。这个 我们建议的目标是揭示ATAD3A控制线粒体功能的机制，使用 果蝇和ATAD3A患者来源的诱导多能干细胞。我们的中心假设是 ATAD3A调节线粒体膜脂稳态，从而调节线粒体膜动力学， 线粒体DNA(MtDNA)复制和脂肪代谢，基于以下令人信服的证据。第一, ATAD3A在内质网-线粒体接触位点(EMCs)的形成中发挥作用，而EMCS是进口所必需的 以及磷脂的合成。其次，ATAD3A也是将胆固醇输入线粒体所必需的 维持富含胆固醇的线粒体膜结构。最后，携带ATAD3A突变的患者 表现出3-甲基谷氨酸排泄增加，这通常是由线粒体缺陷引起的 继发于心磷脂重构缺陷的呼吸复合体。我们希望这种机械的洞察力 我们研究得出的ATADA3突变的结果将揭示意想不到的治疗靶点 用于预防或治疗各种线粒体疾病。我们将通过以下方式测试我们的中心假设 具体目的如下：(1)阐明ATAD3A如何调节线粒体膜动力学； (2)确定ATAD3A如何促进神经元中的mtDNA复制；以及(3)确定ATAD3A如何调节 心脏功能正常。 在我们的研究结束后，我们希望揭示ATAD3A是如何调节线粒体膜的 动力学、生物发生和心脏功能。了解ATAD3A如何连接线粒体的不同方面 生物学有望通过揭示分子基础以及新的治疗方法产生积极影响 ATAD3A相关疾病和其他由线粒体引起的疾病的目标和策略 功能障碍。