Elucidating pathological mechanism of DI-CMTC

描述（由申请人提供）：CMT病是一组特异性影响周围神经系统的遗传性疾病，以进行性肌肉萎缩、感觉丧失和骨骼畸形为特征。这种没有有效治疗方法的遗传性疾病是最常见的遗传性神经系统疾病之一，在美国，大约每2500人中就有1人患有这种疾病，相当于大约12.5万人。四种不同的氨基酰基- trna合成酶基因的多重突变与CMT有因果关系。因此，tRNA合成酶是与CMT相关的最大的基因家族之一。这强调了tRNA合成酶在该病病因学中的重要性。理解CMT和tRNA合成酶之间的联系是一个挑战。由于tRNA合成酶在蛋白质合成中起着至关重要的作用，因此人们一直认为，导致cmt的tRNA合成酶突变一定会以某种方式影响蛋白质合成。有趣的是，cmt引起的突变并不一定影响酶的氨基酰化功能；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，这表明存在功能获得性疾病机制。最后，由于蛋白质合成对所有组织类型都是必需的，与CMT表型相关的极端组织特异性使得对tRNA合成酶在CMT疾病中的作用的生物学理解变得复杂。本项目的目的是确定DI-CMTC的致病机制，DI-CMTC是由酪氨酸tRNA合成酶（TyrRS或YARS）显性突变引起的CMT亚型。通过国际合作和跨学科方法，结合果蝇遗传学、生物化学、细胞和分子生物学的方法，我们将确定YARS突变与DI-CMTC联系的机制。从广义上讲，tRNA合成酶家族代表了一类DNA/RNA结合蛋白，作为一个整体，它们在神经退行性过程中发挥了重要作用，并成为治疗开发的潜在靶点。因此，我们将从目前的研究中获得的机制理解肯定会揭示CMT以外的其他神经系统疾病的病因学。

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.