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.

Friedreich的共济失调（FA）是最常见的隐性共济失调，完成了约一半的患者 共济失调诊所。 FA是由单个线粒体定位蛋白Frataxin的缺乏引起的，约为10％ 该线粒体蛋白质部署的残留以及神经病理生理和心脏病的后果 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着的FA患者的血液淋巴细胞成比例的缺陷， 在FA小鼠模型中，多个神经和肌肉组织的减少。线粒体生物发生的耗竭 功能可能是FA病理生理学和神经变性的主要驱动力，即我们的前提是 frataxin降低→线粒体生成的下降→FA神经病理生理学和神经变性。此外， 因为有线生物发生缺陷发生在活的FA患者的血液淋巴细胞中 缺乏症，它可以提供重要的血液生物标志物病理生理学和/或患者的结果 临床药物试验。我们建议研究有线生成缺陷对产空的贡献 FA，FXNKD鼠标最佳小鼠模型中的病理机制（AIM 1），Frataxin的机制 降低导致有线核病缺陷（AIM 2），以及有线核生成缺陷的相关性和稳定性 活着的FA患者的外周血淋巴细胞，以及自动型FA人类靶标的有线菌缺损 经历神经变性和心脏变性的组织（AIM 3）。这些研究将阐明 线粒体生物发生中frataxin依赖性缺陷的病理力学贡献，我们确定 最佳可用鼠标模型的共济失调及其作为生物标志物的价值及其与 在人类状况下的病理机理。