Jin Peng, Zarnescu Daniela C, Zhang Fuping, Pearson Christopher E, Lucchesi John C, Moses Kevin, Warren Stephen T
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
Neuron. 2003 Aug 28;39(5):739-47. doi: 10.1016/s0896-6273(03)00533-6.
Fragile X syndrome carriers have FMR1 alleles, called premutations, with an intermediate number of 5' untranslated CGG repeats between patients (>200 repeats) and normal individuals (<60 repeats). A novel neurodegenerative disease has recently been appreciated in some premutation carriers. As no neurodegeneration is seen in fragile X patients, who do not express FMR1, we hypothesize that lengthened rCGG repeats of the premutation transcript may lead to neurodegeneration. Here, using Drosophila melanogaster, we show that 90 rCGG repeats alone are sufficient to cause neurodegeneration. This phenotype is neuron specific and rCGG repeat dosage sensitive. Although devoid of mutant protein, this neurodegeneration exhibits neuronal inclusion bodies that are Hsp70 and ubiquitin positive. Overexpression of Hsp70 could suppress the neurodegeneration. These results demonstrate that neurodegenerative phenotype associated with fragile X premutation is indeed caused by the lengthened rCGG repeats and provide the first in vivo experimental demonstration of RNA-mediated neurodegeneration.
脆性X综合征携带者具有FMR1等位基因，称为前突变，其5'非翻译区CGG重复序列的数量介于患者（>200次重复）和正常个体（<60次重复）之间。最近在一些前突变携带者中发现了一种新型神经退行性疾病。由于在不表达FMR1的脆性X患者中未观察到神经退行性变，我们推测前突变转录本延长的rCGG重复序列可能导致神经退行性变。在此，我们利用黑腹果蝇表明，仅90个rCGG重复序列就足以导致神经退行性变。这种表型具有神经元特异性且对rCGG重复剂量敏感。尽管没有突变蛋白，但这种神经退行性变表现出Hsp70和泛素阳性的神经元包涵体。Hsp70的过表达可以抑制神经退行性变。这些结果表明，与脆性X前突变相关的神经退行性表型确实是由延长的rCGG重复序列引起的，并首次在体内实验证明了RNA介导的神经退行性变。
