Hukema Renate K, Buijsen Ronald A M, Raske Chris, Severijnen Lies Anne, Nieuwenhuizen-Bakker Ingeborg, Minneboo Michelle, Maas Alex, de Crom Rini, Kros Johan M, Hagerman Paul J, Berman Robert F, Willemsen Rob
a Department of Clinical Genetics ; Erasmus MC ; Rotterdam , The Netherlands.
Cell Cycle. 2014;13(16):2600-8. doi: 10.4161/15384101.2014.943112.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation forms of the FMR1 gene, resulting in a progressive development of tremor, ataxia and neuropsychological problems. The disease is caused by an expanded CGG repeat in the FMR1 gene, leading to an RNA gain-of-function toxicity mechanism. In order to study the pathogenesis of FXTAS, new inducible transgenic mouse models have been developed that expresses either 11CGGs or 90CGGs at the RNA level under control of a Tet-On promoter. When bred to an hnRNP-rtTA driver line, doxycycline (dox) induced expression of the transgene could be found in almost all tissues. Dox exposure resulted in loss of weight and death within 5 d for the 90CGG RNA expressing mice. Immunohistochemical examination of tissues of these mice revealed steatosis and apoptosis in the liver. Decreased expression of GPX1 and increased expression of cytochrome C is found. These effects were not seen in mice expressing a normal sized 11CGG repeat. In conclusion, we were able to show in vivo that expression of an expanded CGG-repeat rather than overexpression of a normal CGG-repeat causes pathology. In addition, we have shown that expanded CGG RNA expression can cause mitochondrial dysfunction by regulating expression levels of several markers. Although FTXAS patients do not display liver abnormalities, our findings contribute to understanding of the molecular mechanisms underlying toxicity of CGG repeat RNA expression in an animal model. In addition, the dox inducible mouse lines offer new opportunities to study therapeutic interventions for FXTAS.
脆性X相关震颤/共济失调综合征（FXTAS）是一种迟发性神经退行性疾病，影响FMR1基因前突变形式的携带者，导致震颤、共济失调和神经心理问题的进行性发展。该疾病由FMR1基因中CGG重复序列的扩增引起，导致RNA功能获得性毒性机制。为了研究FXTAS的发病机制，已经开发了新的诱导型转基因小鼠模型，该模型在Tet-On启动子的控制下在RNA水平表达11个CGG或90个CGG。当与hnRNP-rtTA驱动系杂交时，在几乎所有组织中都可以发现强力霉素（dox）诱导的转基因表达。暴露于dox导致表达90个CGG RNA的小鼠在5天内体重减轻并死亡。对这些小鼠的组织进行免疫组织化学检查发现肝脏有脂肪变性和细胞凋亡。发现GPX1表达降低，细胞色素C表达增加。在表达正常大小的11个CGG重复序列的小鼠中未观察到这些效应。总之，我们能够在体内证明，扩增的CGG重复序列的表达而非正常CGG重复序列的过表达会导致病理变化。此外，我们已经表明，扩增的CGG RNA表达可以通过调节几种标志物的表达水平来引起线粒体功能障碍。虽然FXTAS患者没有表现出肝脏异常，但我们的发现有助于理解动物模型中CGG重复RNA表达毒性的分子机制。此外，dox诱导的小鼠品系为研究FXTAS的治疗干预提供了新的机会。
