Extra-translational roles of aminoacyl tRNA synthetases in connection to disease

摘要 Charcot-Marie-Tooth(CMT)病是最常见的遗传性疾病 周围神经病，大约每2500人中就有一人受到影响，相当于 美国大约有12.5万人。CMT没有有效的治疗方法 目前存在。这些疾病特别影响周围神经系统，并且是 以进行性运动神经元变性、肌肉萎缩和感觉为特征 损失。神经遗传学研究的最新进展揭示了氨基酰tRNA 合成酶是与CMT相关的最大基因家族。其中，GAR、编码 甘氨酰-tRNA合成酶(GlyRS)是第一个被发现并发生突变的成员 导致显性轴索形式的CMT(CMT2D)。尽管有广泛的要求 GlyRS对于所有细胞中的蛋白质生物合成，该基因的突变导致选择性 外周轴突变性导致远端运动功能障碍。 该项目的目标是确定CMT2D的致病机制。我们的 中心假设是CMT2D引起的突变体GlyRS获得了异常的结合 直接拮抗运动神经元基本信号通路的活动 而突变的GlyRS的毒性功能可能与一种调节失调的， 野生型GlyRS的翻译外功能。我们的假设是基于我们的结果 从这笔赠款的上一个资助期以及我们与其他 实验室。通过一系列的方法，从氢-氚交换 分析，X射线结晶学，生化和细胞分析对小鼠的研究， 该项目不仅将阐明CMT2D的引发机制，并为 为CMT2D患者制定治疗策略，但也揭示了重要的 GlyRSWT在蛋白质中的经典酶功能以外的调节功能 综合。

Abstract Charcot-Marie-Tooth (CMT) diseases are the most common form of hereditary peripheral neuropathies, affecting approximately 1 in 2,500 people equating to approximately 125,000 people in the United States. No effective therapy for CMT currently exists. The diseases specifically affect the peripheral nervous system and are characterized by progressive motor neuron degeneration, muscle atrophy, and sensory loss. Recent progress in neurogenetic studies has uncovered aminoacyl-tRNA synthetase as the largest gene family implicated in CMT. Among them, GARS, encoding glycyl-tRNA synthetase (GlyRS), is the first member identified and whose mutations cause a dominant axonal form of CMT (CMT2D). Despite the broad requirement of GlyRS for protein biosynthesis in all cells, mutations in this gene cause a selective degeneration of peripheral axons leading to deficits in distal motor function. The goal of this project is to determine the disease-causing mechanism for CMT2D. Our central hypothesis is that CMT2D-causing mutant GlyRS acquires an aberrant binding activity that directly antagonizes an essential signaling pathway for motor neuron survival, and that the toxic function of mutant GlyRS may be linked to a dysregulated, extra-translational function of wild-type GlyRS. Our hypothesis is based on our results from the previous funding period of this grant and from our collaborations with other laboratories. Through a broad range of methods from hydrogen-deuterium exchange analysis, X-ray crystallography, biochemical, and cell-based analysis to mice studies, this project will not only shed light on CMT2D causing mechanisms and open doors for developing therapeutic strategies for CMT2D patients, but also reveal important regulatory functions of GlyRSWT beyond its classic enzymatic function in protein synthesis.