Elucidating pathological mechanism of DI-CMTC

描述（由申请人提供）：腓骨肌萎缩症（CMT）是一组遗传性疾病，专门影响周围神经系统，其特征为进行性肌肉萎缩、感觉丧失和骨畸形。这种遗传性疾病，没有有效的治疗方法，是最常见的遗传性神经系统疾病之一，影响约1/2500的人，相当于美国约125,000人。四种不同氨酰-tRNA合成酶基因的多个突变与CMT有因果关系。因此，tRNA合成酶是与CMT相关的最大基因家族之一。这强调了tRNA合成酶在疾病病因学中的重要性。了解CMT和tRNA合成酶之间的联系是一个挑战。由于tRNA合成酶是蛋白质合成的重要参与者，因此一直以来的教条是，tRNA合成酶中引起CMT的突变必须以某种方式影响蛋白质合成。有趣的是，CMT引起的突变不一定会影响酶的氨酰化功能;几乎所有与CMT相关的tRNA合成酶突变都具有常染色体显性特征，这表明功能获得性疾病机制。最后，由于蛋白质合成对于所有组织类型都是必不可少的，因此与CMT表型相关的极端组织特异性使对tRNA合成酶在CMT疾病中的作用的生物学理解变得复杂。本项目的目标是确定DI-CMTC的致病机制，DI-CMTC是由酪氨酸tRNA合成酶（TyrRS或YARS）的显性突变引起的CMT亚型。通过国际合作和结合果蝇遗传学，生物化学和细胞与分子生物学方法的跨学科方法，我们将定义YARS突变与DI-CMTC相关的机制。一般来说，tRNA合成酶家族代表一类DNA/RNA结合蛋白，其作为一个整体已成为神经退行性过程中的重要参与者和治疗开发的潜在靶点。因此，我们从当前研究中获得的机制理解肯定会揭示除了CMT之外的其他神经系统疾病的病因。

DESCRIPTION (provided by applicant): Charcot-Marie-Tooth (CMT) disease is a group of inherited disorders that specifically affect the peripheral nerves system and is characterized by progressive muscle atrophy, sensory loss and bone deformities. This genetic disease, for which there is no effective therapy, is one of the most commonly inherited neurological disorders affecting approximately 1 in 2,500 people equating to approximately 125,000 people in the United States. Multiple mutations in four different aminoacyl-tRNA synthetase genes are causally linked to CMT. Thus tRNA synthetases are one of the largest gene families associated with CMT. This underscores the importance of tRNA synthetase in the etiology of the disease. Understanding the connection between CMT and tRNA synthetases is a challenge. Because tRNA synthetases are essential players in protein synthesis, the dogma has been that the CMT-causing mutations in tRNA synthetases must affect protein synthesis in some way. Intriguingly, CMT-causing mutations do not necessarily affect the aminoacylation function of the enzyme; and almost all tRNA synthetase mutations that are CMT-associated have autosomal dominant trait, suggesting a gain-of-function disease mechanism. Lastly, as protein synthesis is essential for all tissue types, the extreme tissue specificity associated with the CMT phenotypes has complicated the biological understanding of the role of tRNA synthetases in CMT disease. The goal of this project is to determine the disease-causing mechanism for DI-CMTC, a subtype of CMT caused by dominant mutations in tyrosine tRNA synthetase (TyrRS or YARS). Through international collaborations and a cross-disciplinary approach that combines methods of Drosophila genetics, biochemistry and cell and molecular biology, we will define the mechanism through which YARS mutations are linked to DI-CMTC. Broadly speaking, the tRNA synthetase family represents one class of DNA/RNA binding proteins that, as a whole, have emerged as an important player in neurodegenerative processes and as potential targets for therapeutic development. Thus, the mechanistic understanding we will obtain from the current study would certainly shed light on the etiology of other neurological disorders beyond CMT.