Friedreich's ataxia, mitochondrial biogenesis, and neurodegeneration

弗里德赖希共济失调（FA）是最常见的隐性遗传性共济失调，包括约一半的患者看到， 共济失调诊所。FA是由一种单一的脑内定位蛋白（frataxin）缺乏引起的，约10% 残留的，以及这种线粒体蛋白质缺失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第一次证明了线粒体的生物起源 与活FA患者的FA患者成纤维细胞和血液淋巴细胞中的共济失调蛋白缺陷成比例的缺陷，以及 在FA小鼠模型中，多种神经和肌肉组织中的含量降低。这种线粒体生物合成的损耗 和功能可能是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 即共济失调蛋白下降→有丝分裂原性下降→FA神经病理生理学和神经退行性变。此外，委员会认为， 因为活的FA患者的血液淋巴细胞中发生的有丝分裂发生缺陷与他们的共济失调成比例， 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， 临床药物试验因此，我们建议研究有丝分裂生物缺陷对共济失调的贡献。 在FA的最佳小鼠模型FXNKD小鼠（Aim 1）中，研究了共济失调蛋白 减少导致有丝分裂生物缺陷（目的2），以及有丝分裂生物缺陷的相关性和稳定性， 活FA患者的外周血淋巴细胞，以及尸检FA人靶细胞中的有丝分裂生物学缺陷 经历神经变性和心脏变性的组织（目标3）。这些研究将阐明 我们确定了线粒体生物发生中共济失调蛋白依赖性缺陷的病理机制贡献， 共济失调在FA的最佳小鼠模型中的作用，及其作为生物标志物的价值，及其与 人类的病理机制

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.