Peripheral neuropathy via mutant tRNA synthetases: Inhibition of protein translation provides a possible explanation.
Peripheral neuropathy via mutant tRNA synthetases: Inhibition of protein translation provides a possible explanation.
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DOI：
10.1002/bies.201600052
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发表时间：
2016-09
期刊：
影响因子：
4
通讯作者：
Storkebaum, Erik
中科院分区：
文献类型：
--
作者：
Storkebaum, Erik
关键词：
最近的证据表明，蛋白质翻译的抑制可能是突变型tRNA合成酶(AARS)相关周围神经病的常见致病机制。AARS是一种将氨基酸与其同源tRNA连接起来的酶，从而催化翻译的第一步。5个不同的AARs的显性突变导致夏科-玛丽-牙(Charcot-Marie-Tooth，CMT)周围神经病，其特征是周围运动和感觉轴突的长度依赖性退化。令人惊讶的是，突变的AARS不需要失去氨基酰化活性就能引起CMT。相反，至少对于某些突变来说，CMT-AARS的基础是一种毒性功能获得机制。有趣的是，最近在CMT-AARS的果蝇模型中，两个不同的AARS上的几个突变被证明通过一种独立于氨基酰化的机制抑制了整体蛋白质的翻译，这表明翻译抑制是一种常见的致病机制。未来的研究旨在阐明CMT突变的AARS导致翻译缺陷的分子机制，这将为这些无法治愈的疾病的分子发病机制提供新的见解。
Recent evidence indicates that inhibition of protein translation may be a common pathogenic mechanism for peripheral neuropathy associated with mutant tRNA synthetases (aaRSs). aaRSs are enzymes that ligate amino acids to their cognate tRNA, thus catalyzing the first step of translation. Dominant mutations in five distinct aaRSs cause Charcot‐Marie‐Tooth (CMT) peripheral neuropathy, characterized by length‐dependent degeneration of peripheral motor and sensory axons. Surprisingly, loss of aminoacylation activity is not required for mutant aaRSs to cause CMT. Rather, at least for some mutations, a toxic‐gain‐of‐function mechanism underlies CMT‐aaRS. Interestingly, several mutations in two distinct aaRSs were recently shown to inhibit global protein translation in Drosophila models of CMT‐aaRS, by a mechanism independent of aminoacylation, suggesting inhibition of translation as a common pathogenic mechanism. Future research aimed at elucidating the molecular mechanisms underlying the translation defect induced by CMT‐mutant aaRSs should provide novel insight into the molecular pathogenesis of these incurable diseases.
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影响因子：
14.8
作者：
Guo, Min;Schimmel, Paul
通讯作者：
Schimmel, Paul
DOI：
10.1136/jnnp-2013-305049
发表时间：
2013-11
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
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作者：
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通讯作者：
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影响因子：
9.8
作者：
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通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
Green, Eric D.
影响因子：
9.9
作者：
Del Bo, R;Locatelli, F;Comi, GP
通讯作者：
Comi, GP