Ectopic expression of CGG containing mRNA is neurotoxic in mammals
Ectopic expression of CGG containing mRNA is neurotoxic in mammals
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DOI：
10.1093/hmg/ddp182
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发表时间：
2009-07-01
影响因子：
3.5
通讯作者：
Nelson, David L.
中科院分区：
文献类型：
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作者：
Hashem, Vera;Galloway, Jocelyn N.;Nelson, David L.
脆性X相关震颤/共济失调综合征（FXTAS）是一种进行性神经退行性疾病，已在相当一部分老年男性脆性X前兆携带者中被诊断出来。受FXTAS影响的患者血液白细胞中含有FMR1 mRNA的核糖- rcgg重复序列水平升高，FMRP水平正常至轻微降低。再加上脆性X综合征患者中缺乏FXTAS，这表明FMR1转录物中突变前大小的延长的rCGG重复序列，而不是FMRP水平的改变，是FXTAS病理的原因。在Fmr1或浦肯野神经元中特异性增强的绿色荧光蛋白背景下表达rCGG的小鼠被生成，以分离rCGG与Fmr1改变的影响，并提供证据证明rCGG是引起类似人类FXTAS病理的必要和充分条件。模型显示浦肯野神经元核内包涵体的存在，浦肯野神经元细胞死亡和行为缺陷。这些结果表明，在哺乳动物系统中，Purkinje神经元中不含Fmr1 mRNA的rCGG表达可导致神经元病理，并表明RNA中CGG重复序列的扩增可能是FXTAS神经退行性变的原因。
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a progressive neurodegenerative disorder that has been diagnosed in a substantial fraction of older male fragile X premutation carriers. Patients affected by FXTAS have elevated levels of ribo-rCGG repeat containing FMR1 mRNA with normal to slightly reduced levels of FMRP in blood leukocytes. Coupled with the absence of FXTAS in fragile X syndrome patients, this suggests premutation-sized elongated rCGG repeats in the FMR1 transcript rather than alterations in the levels of FMRP are responsible for the FXTAS pathology. Mice expressing rCGG in the context of Fmr1 or the enhanced green fluorescent protein specifically in Purkinje neurons were generated to segregate the effects of rCGG from alterations in Fmr1 and to provide evidence that rCGG is necessary and sufficient to cause pathology similar to human FXTAS. The models exhibit the presence of intranuclear inclusions in Purkinje neurons, Purkinje neuron cell death and behavioral deficits. These results demonstrate that rCGG expressed in Purkinje neurons outside the context of Fmr1 mRNA can result in neuronal pathology in a mammalian system and demonstrate that expanded CGG repeats in RNA are the likely cause of the neurodegeneration in FXTAS.