Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in Drosophila
Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in Drosophila
复制标题
化学筛选揭示小分子抑制果蝇脆性X前突变rCGG重复介导的神经变性
DOI：
10.1093/hmg/dds024
复制
发表时间：
2012-05-01
影响因子：
3.5
通讯作者：
Jin, Peng
中科院分区：
文献类型：
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作者：
Qurashi, Abrar;Liu, Huijie;Jin, Peng
脆性X相关震颤/共济失调综合征（FXTAS）是脆性X前突变携带者中发现的一种进行性神经退行性疾病。使用果蝇，我们以前确定延长非编码CGG重复FMR 1等位基因的致病原因FXTAS。在这里，我们使用相同的FXTAS果蝇模型进行化学筛选，揭示了可以减轻脆性X前突变核糖CGG（rCGG）重复序列毒性作用的小分子，其中包括几种已知的磷脂酶A（2）（PLA（2））抑制剂。我们发现，特异性抑制PLA（2）活性可以减轻脆性X前突变rCGG重复序列引起的神经元缺陷，包括致死性和运动缺陷。此外，通过遗传筛选，我们确定了一个PLA（2）果蝇直系同源物，专门调节rCGG重复介导的神经元毒性。我们的结果证明了果蝇模型用于无偏小分子筛选的实用性，并指出PLA（2）作为治疗FXTAS的可能治疗靶点。
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder recognized in fragile X premutation carriers. Using Drosophila, we previously identified elongated non-coding CGG repeats in FMR1 allele as the pathogenic cause of FXTAS. Here, we use this same FXTAS Drosophila model to conduct a chemical screen that reveals small molecules that can ameliorate the toxic effects of fragile X premutation ribo-CGG (rCGG) repeats, among them several known phospholipase A(2) (PLA(2)) inhibitors. We show that specific inhibition of PLA(2) activity could mitigate the neuronal deficits caused by fragile X premutation rCGG repeats, including lethality and locomotion deficits. Furthermore, through a genetic screen, we identified a PLA(2) Drosophila ortholog that specifically modulates rCGG repeat-mediated neuronal toxicity. Our results demonstrate the utility of Drosophila models for unbiased small molecule screens and point to PLA(2) as a possible therapeutic target to treat FXTAS.