Mitochondria, Metals and Oxidative Stress Laboratory, Institut Jacques Monod (UMR 7592 CNRS-University Paris-Diderot), Paris, France.
Antioxid Redox Signal. 2010 Sep 1;13(5):651-90. doi: 10.1089/ars.2009.3015.
Mitochondrial dysfunction and oxidative damage are at the origin of numerous neurodegenerative diseases like Friedreich ataxia and Alzheimer and Parkinson diseases. Friedreich ataxia (FRDA) is the most common hereditary ataxia, with one individual affected in 50,000. This disease is characterized by progressive degeneration of the central and peripheral nervous systems, cardiomyopathy, and increased incidence of diabetes mellitus. FRDA is caused by a dynamic mutation, a GAA trinucleotide repeat expansion, in the first intron of the FXN gene. Fewer than 5% of the patients are heterozygous and carry point mutations in the other allele. The molecular consequences of the GAA triplet expansion is transcription silencing and reduced expression of the encoded mitochondrial protein, frataxin. The precise cellular role of frataxin is not known; however, it is clear now that several mitochondrial functions are not performed correctly in patient cells. The affected functions include respiration, iron-sulfur cluster assembly, iron homeostasis, and maintenance of the redox status. This review highlights the molecular mechanisms that underlie the disease phenotypes and the different hypothesis about the function of frataxin. In addition, we present an overview of the most recent therapeutic approaches for this severe disease that actually has no efficient treatment.
线粒体功能障碍和氧化损伤是许多神经退行性疾病的根源，如弗里德里希共济失调和阿尔茨海默病和帕金森病。弗里德里希共济失调（FRDA）是最常见的遗传性共济失调，每 50,000 人中就有 1 人受到影响。这种疾病的特征是中枢和周围神经系统的进行性退化、心肌病和糖尿病发病率的增加。FRDA 是由 FXN 基因第一个内含子中 GAA 三核苷酸重复扩展引起的动态突变引起的。不到 5%的患者是杂合子，另一个等位基因携带点突变。GAA 三核苷酸扩展的分子后果是转录沉默和编码线粒体蛋白 frataxin 的表达减少。frataxin 的精确细胞功能尚不清楚；然而，现在很清楚，患者细胞中的几种线粒体功能不能正常发挥。受影响的功能包括呼吸、铁硫簇组装、铁稳态和氧化还原状态的维持。这篇综述强调了疾病表型的分子机制以及 frataxin 功能的不同假设。此外，我们还介绍了针对这种严重疾病的最新治疗方法的概述，该疾病实际上没有有效的治疗方法。
