Friedreich's ataxia, mitochondrial biogenesis, and neurodegeneration

弗里德赖希共济失调、线粒体生物发生和神经变性

• 批准号: 9765713
• 负责人: Gino A Cortopassi
• 金额: $ 43.16万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765713
• 关键词: Address; Animal Model; Ataxia; Biogenesis; Biological Assay; Biological Markers; Blood; Brain; Cell model; Cerebellum; Clinic; Clinical; Clinical Trials; Defect; Disease; Doxycycline; Enzymes; Fibroblasts; Friedreich Ataxia; Functional disorder; Genes; Goals; Heart; Human; Inflammation; Inherited; Iron; Link; Lymphocyte; Methods; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modeling; Mus; Muscle; Nerve Degeneration; Patient-Focused Outcomes; Patients; Peripheral Blood Lymphocyte; Pharmaceutical Preparations; Phenotype; Proteins; Publishing; Recording of previous events; Recovery; Residual state; Severities; Spinal Ganglia; Sulfur; Time; Tissues; Trees; Work; brain tissue; experience; frataxin; human tissue; insight; knock-down; mouse model; neurobehavioral; neurophysiology; relating to nervous system; small hairpin RNA

Friedreich's ataxia (FA) is the most common recessive inherited ataxia, comprising about half of patients seen in ataxia clinics. FA is caused by the deficiency of a single mitochondrially-localized protein, frataxin, to about 10% residual, and the neuropathophysiological and cardiological consequences of this mitochondrial protein depletion are ultimately lethal. We have recently demonstrated for the first time that there is a mitochondrial biogenesis defect proportional to the frataxin defect in FA patient fibroblasts and blood lymphocytes of living FA patients, and decreased in multiple neural and muscle tissues in FA mouse models. This depletion of mitochondrial biogenesis and function could turn out to be a major driver of FA pathophysiology and neurodegeneration, i.e. our premise is that frataxin decline→mitobiogenic decline→FA neuropathophysiology and neurodegeneration. Furthermore, because the mitobiogenesis defect occurs in blood lymphocytes of living FA patients in proportion to their frataxin deficiency, it could provide an important blood biomarker of disease pathophysiology and/or patient outcome for clinical drug trials. Thus we propose to investigate the contribution of the mitobiogenic defect to the ataxic pathomechanism in the best mouse model of FA, the FXNKD mouse (Aim 1), the mechanism by which frataxin decrease leads to the mitobiogenic defect (Aim 2), and the relevance and stability of the mitobiogenic defect in peripheral blood lymphocytes of living FA patients, and also mitobiogenic defects in autoptic FA human target tissues that experience neurodegeneration and cardiodegeneration (Aim 3). These studies will clarify the pathomechanistic contribution of the frataxin-dependent defect in mitochondrial biogenesis we identified to the ataxia in the best available mouse model of FA, and its value as a biomarker, and its relationship to the pathomechanism in the human condition.

弗里德赖希共济失调 (FA) 是最常见的隐性遗传性共济失调，约占该病患者的一半 FA 是由一种线粒体定位蛋白 frataxin 缺乏约 10% 引起的。 残留，以及这种线粒体蛋白消耗的神经病理生理学和心脏病学后果 最终是致命的。我们最近首次证明存在线粒体生物发生。 与 FA 患者成纤维细胞和活体 FA 患者的血液淋巴细胞中的 frataxin 缺陷成比例的缺陷，以及 FA 小鼠模型中多个神经和肌肉组织中线粒体生物发生的减少。 并且功能可能成为 FA 病理生理学和神经退行性变的主要驱动因素，即我们的前提是 frataxin下降→有丝分裂原下降→FA神经病理生理学和神经变性。 因为活体 FA 患者的血液淋巴细胞中发生的有丝分裂缺陷与其 frataxin 成比例 缺乏，它可以提供疾病病理生理学和/或患者结果的重要血液生物标志物 因此，我们建议研究有丝分裂缺陷对共济失调的影响。 FA 最佳小鼠模型 FXNKD 小鼠（目标 1）的病理机制，frataxin 的机制 减少导致有丝分裂缺陷（目标 2），以及有丝分裂缺陷的相关性和稳定性 活体 FA 患者的外周血淋巴细胞，以及自动 FA 人类目标的有丝分裂缺陷 这些研究将阐明经历神经变性和心脏变性的组织。 我们确定了线粒体生物发生中 frataxin 依赖性缺陷的病理机制贡献 现有最佳 FA 小鼠模型中的共济失调及其作为生物标志物的价值及其与 人类状况的病理机制。