Inserm, U676, Physiopathology and Therapy of Mitochondrial Diseases Laboratory, CHU - Hôpital Robert Debré, 48, boulevard Sérurier, F-75019 Paris, France.
BMC Med. 2011 Oct 11;9:112. doi: 10.1186/1741-7015-9-112.
Friedreich's ataxia, the most frequent progressive autosomal recessive disorder involving the central and peripheral nervous systems, is mostly associated with unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene, which encodes the mitochondrial frataxin protein. Since FXN was shown to be involved in Friedreich's ataxia in the late 1990s, the consequence of frataxin loss of function has generated vigorous debate. Very early on we suggested a unifying hypothesis according to which frataxin deficiency leads to a vicious circle of faulty iron handling, impaired iron-sulphur cluster synthesis and increased oxygen radical production. However, data from cell and animal models now indicate that iron accumulation is an inconsistent and late event and that frataxin deficiency does not always impair the activity of iron-sulphur cluster-containing proteins. In contrast, frataxin deficiency appears to be consistently associated with increased sensitivity to reactive oxygen species as opposed to increased oxygen radical production. By compiling the findings of fundamental research and clinical observations we defend here the opinion that the very first consequence of frataxin depletion is indeed an abnormal oxidative status which initiates the pathogenic mechanism underlying Friedreich's ataxia.
弗里德赖希共济失调是最常见的累及中枢和周围神经系统的常染色体隐性进行性遗传病，主要与 FXN 基因第一内含子中 GAA 三核苷酸重复不稳定扩增有关，该基因编码线粒体 frataxin 蛋白。自 20 世纪 90 年代末 FXN 被证实与弗里德赖希共济失调有关以来，frataxin 功能丧失的后果引发了激烈的争论。很早以前，我们就提出了一个统一的假说，即 frataxin 缺乏导致铁处理错误、铁硫簇合成受损和氧自由基产生增加的恶性循环。然而，来自细胞和动物模型的数据表明，铁积累是一个不一致和晚期的事件，而且 frataxin 缺乏并不总是损害含铁硫簇蛋白的活性。相反，frataxin 缺乏似乎与对活性氧的敏感性增加而不是氧自由基产生增加一致。通过整合基础研究和临床观察的结果，我们在这里捍卫这样一种观点，即 frataxin 耗竭的第一个后果确实是异常的氧化状态，它启动了弗里德赖希共济失调的致病机制。
