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

摘要 腓骨肌萎缩症（CMT）是最常见的遗传性 周围神经病变，影响约1/2，500人，相当于 在美国大约有125，000人。CMT无有效治疗 目前存在。这些疾病特别影响周围神经系统， 其特征在于进行性运动神经元变性、肌肉萎缩和感觉神经元变性。 损失神经遗传学研究的最新进展揭示了氨酰-tRNA 合成酶作为最大的基因家族参与CMT。其中，加尔斯、编码 甘氨酰-tRNA合成酶（GlyRS）是第一个被鉴定的成员，其突变 导致CMT的显性轴突形式（CMT 2D）。尽管有广泛的要求， GlyRS在所有细胞中用于蛋白质生物合成，该基因的突变导致选择性的 导致远端运动功能缺陷的外周轴突变性。 该项目的目标是确定CMT 2D的致病机制。我们 中心假设是CMT 2D引起的突变体GlyRS获得异常结合 直接拮抗运动神经元的基本信号通路的活性 存活，并且突变GlyRS的毒性功能可能与一种失调， 野生型GlyRS的翻译外功能。我们的假设是基于我们的研究结果 从这个赠款的前一个资助期，以及我们与其他合作， laboratories.通过广泛的方法从氢氘交换 分析，X射线晶体学，生物化学和基于细胞的分析，对小鼠的研究， 该项目不仅将揭示CMT 2D的产生机制， 为CMT 2D患者制定治疗策略，但也揭示了重要的 GlyRSWT的调节功能超出了其在蛋白质中的经典酶促功能 合成.

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.