Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome.
Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome.
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DOI：
10.1016/j.neuron.2017.07.013
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发表时间：
2017-08-02
期刊：
影响因子：
16.2
通讯作者：
Osterweil EK
中科院分区：
文献类型：
--
作者：
Thomson SR;Seo SS;Barnes SA;Louros SR;Muscas M;Dando O;Kirby C;Wyllie DJA;Hardingham GE;Kind PC;Osterweil EK
I组代谢性谷氨酸受体（mGlu1/5）下游过度的mRNA翻译是脆性X综合征（FX）的核心病理生理机制；然而，导致神经功能改变的差异翻译mrna尚不清楚。我们使用翻译核糖体亲和纯化（TRAP）和RNA-seq技术鉴定FX小鼠模型（Fmr1−/y）海马CA1锥体神经元中的误翻译mrna，这些mrna表现出夸大的mglu1 /5诱导的长期突触抑制（LTD）。在这些神经元中，我们发现编码毒蕈碱乙酰胆碱受体4 （M4）的Chrm4转录物被过度翻译，mGlu5激活下游的M4合成被模仿和阻断。令人惊讶的是，M4活性的增强而不是抑制使Fmr1−/y的核心表型正常化，包括过度的蛋白质合成，夸张的mGluR-LTD和听源性癫痫。这些结果表明，Fmr1−/y脑中并非所有过度翻译的mrna都是有害的，其中一些可能是增强以纠正FX脑病理变化的候选者。在Fmr1 - /y锥体神经元中，毒毒碱受体M4在Fmr1 - /y海马中被过度翻译。M4的增强而不是抑制纠正了Fmr1 - /y小鼠的核心表型。并非所有过度翻译的mrna都对Fmr1 - /y脑功能有害。Thomson等人使用trapseq鉴定了Fmr1 - /y神经元中毒毒碱受体M4的过度翻译。令人惊讶的是，增强而不是抑制M4纠正神经系统Fmr1 - /y表型。这表明FX脑中某些mrna翻译的升高可能是保护性的，而不是病理性的。
Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu1/5) is a core pathophysiology of fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used translating ribosome affinity purification (TRAP) and RNA-seq to identify mistranslating mRNAs in CA1 pyramidal neurons of the FX mouse model (Fmr1−/y) hippocampus, which exhibit exaggerated mGlu1/5-induced long-term synaptic depression (LTD). In these neurons, we find that the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M4) is excessively translated, and synthesis of M4 downstream of mGlu5 activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M4 activity normalizes core phenotypes in the Fmr1−/y, including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1−/y brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain. TRAP-seq reveals altered translation of >120 mRNAs in Fmr1−/y CA1 pyramidal neurons Muscarinic receptor M4 is excessively translated in Fmr1−/y hippocampus Enhancement, not inhibition, of M4 corrects core phenotypes in the Fmr1−/y mouse Not all excessively translating mRNAs are detrimental to Fmr1−/y brain function Thomson et al. use TRAP-seq to identify excessive translation of muscarinic receptor M4 in Fmr1−/y neurons. Surprisingly, enhancement rather than inhibition of M4 corrects neurological Fmr1−/y phenotypes. This suggests that elevated translation of certain mRNAs in the FX brain may be protective rather than pathological.
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影响因子：
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