Cooper J M, Schapira A H V
University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK.
Mitochondrion. 2007 Jun;7 Suppl:S127-35. doi: 10.1016/j.mito.2007.04.001. Epub 2007 Apr 7.
Since the identification of the genetic mutation causing Friedreich's ataxia (FRDA) our understanding of the mechanisms underlying disease pathogenesis have improved markedly. The genetic abnormality results in the deficiency of frataxin, a protein targeted to the mitochondrion. There is extensive evidence that mitochondrial respiratory chain dysfunction, oxidative damage and iron accumulation play significant roles in the disease mechanism. There remains considerable debate as to the normal function of frataxin, but it is likely to be involved in mitochondrial iron handling, antioxidant regulation, and/or iron sulphur centre regulation. Therapeutic avenues for patients with FRDA are beginning to be explored in particular targeting antioxidant protection, enhancement of mitochondrial oxidative phosphorylation, iron chelation and more recently increasing FRDA transcription. The use of quinone therapy has been the most extensively studied to date with clear benefits demonstrated using evaluations of both disease biomarkers and clinical symptoms, and this is the topic that will be covered in this review.
自从导致弗里德赖希共济失调(FRDA)的基因突变被发现以来,我们对该疾病发病机制的理解有了显著提高。这种基因异常导致了frataxin的缺乏,frataxin是一种定位于线粒体的蛋白质。有大量证据表明,线粒体呼吸链功能障碍、氧化损伤和铁积累在疾病机制中起重要作用。关于frataxin的正常功能仍存在相当大的争议,但它可能参与线粒体铁处理、抗氧化调节和/或铁硫中心调节。针对FRDA患者的治疗途径正在开始探索,特别是针对抗氧化保护、增强线粒体氧化磷酸化、铁螯合,以及最近增加FRDA转录。醌类疗法是迄今为止研究最广泛的,通过对疾病生物标志物和临床症状的评估都证明了其明显益处,这也是本综述将涵盖的主题。