Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India.
Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université of Strasbourg, 67400 Illkirch, France.
Biochim Biophys Acta Mol Basis Dis. 2020 Dec 1;1866(12):165918. doi: 10.1016/j.bbadis.2020.165918. Epub 2020 Aug 12.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by an expansion of 55-200 CGG repeats at 5UTR of FMR1 gene, known as premutation. The main clinical and neuropathological features of FXTAS include progressive intention tremor, gait ataxia, neuronal cell loss and presence of ubiquitin-positive intranuclear inclusions in neurons and astrocytes. Various mitochondrial dysfunctions are reported in in vitro/vivo models of FXTAS; however, the molecular mechanisms underlying such mitochondrial dysfunctions are unclear. CGG expansions are pathogenic through distinct mechanisms involving RNA gain of function, impaired DNA damage repair and FMRpolyG toxicity. Here, we have systematically reviewed the reports of mitochondrial dysfunctions under premutation condition. We have also focused on potential emerging mechanisms to understand mitochondrial associated pathology in FXTAS. This review highlights the important role of mitochondria in FXTAS and other related disorders; and suggests focus of future studies on mitochondrial dysfunction along with other prevailing mechanisms to alleviate neurodegeneration.
脆性 X 相关震颤共济失调综合征（FXTAS）是一种遗传性神经退行性疾病，由 FMR1 基因 5'UTR 处的 55-200 个 CGG 重复扩增引起，称为前突变。FXTAS 的主要临床和神经病理学特征包括进行性意向性震颤、步态共济失调、神经元细胞丢失以及神经元和星形胶质细胞中存在泛素阳性核内包涵体。在 FXTAS 的体外/体内模型中报道了各种线粒体功能障碍；然而，这种线粒体功能障碍的分子机制尚不清楚。CGG 扩增通过涉及 RNA 获得功能、DNA 损伤修复受损和 FMRpolyG 毒性的不同机制具有致病性。在这里，我们系统地回顾了前突变条件下线粒体功能障碍的报告。我们还重点关注了潜在的新兴机制，以了解 FXTAS 中的线粒体相关病理学。该综述强调了线粒体在 FXTAS 和其他相关疾病中的重要作用；并建议未来的研究集中在与其他流行机制一起缓解神经退行性变的线粒体功能障碍上。
