Exploring the functions of tRNA synthetases in the nucleus and their relationship to CMT

探索细胞核中 tRNA 合成酶的功能及其与 CMT 的关系

• 批准号: 10227442
• 负责人: Robert W Burgess
• 金额: $ 9.43万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227442
• 关键词: Affect; Alleles; Alzheimer' s Disease; Amino Acids; Amino Acyl-tRNA Synthetases; Aminoacylation; Amyotrophic Lateral Sclerosis; Biological; Biological Models; Biological Process; Blood Vessels; Body Weight; Cell Nucleus; Charcot-Marie-Tooth Disease; Chromosomes; Data; Deformity; Development; Disease; Distal; Drosophila genus; Engineering; Enzymes; Eukaryotic Cell; Gene Family; Genetic Transcription; Goals; HDAC1 gene; Hereditary Motor and Sensory Neuropathies; Heterozygote; Hindlimb; Homozygote; Huntington Disease; Inflammation; Inherited; Knock-in; Knowledge; Lead; Length; Limb structure; Link; Modeling; Mus; Muscle; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuropathy; Nuclear; Nuclear Translocation; Oxidative Stress; Parkinson Disease; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System Diseases; Phenotype; Physiological; Prevalence; Process; Protein Biosynthesis; Reaction; Reagent; Regulator Genes; Role; Sensory; Specificity; System; Tissues; Transfer RNA; Transfer RNA Aminoacylation; United States; Weight maintenance regimen; YARS gene; biological adaptation to stress; gain of function; in vivo; in vivo Model; motor impairment; mouse model; multiple omics; mutant; nervous system disorder; novel; skeletal; wasting

Abstract Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and sensory neuropathy (HMSN), is the most common form of inherited peripheral neuropathy, with an estimated prevalence of 1 in 2500 people, equating to approximately 125,000 people in the United States. CMT affects peripheral nerves in a length- dependent manner and is characterized by weakness and wasting of the distal limb muscles leading to progressive motor impairment, sensory loss, and skeletal deformities. No therapy is available for CMT patients. The largest gene family implicated in CMT encodes aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes that catalyze the first reaction in protein biosynthesis, namely, the charging of transfer RNAs (tRNAs) with their cognate amino acids. However, understanding the connection between CMT and aaRSs is a challenge. Because aaRSs are essential players in protein synthesis, it is believed that the CMT-causing mutations in tRNA synthetases must affect protein synthesis in some way. Curiously, 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 inheritance, 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 aaRSs in CMT disease. Intriguingly, cytosolic aaRSs are also detected in the nucleus of eukaryotic cells. While the initial hypothesis was that aaRSs function here in proofreading newly-synthesized tRNAs, later findings suggest that the nuclear-localized aaRSs are involved in regulating a wide range of biological processes including vascular development, inflammation, and stress responses mainly due to their distinctive abilities to interact with the transcriptional machinery. However, the biological function of nuclear TyrRS has never been investigated in vivo in a mammalian system. The goal of this project is to explore the physiological functions of aaRSs in the nucleus and their relationship to CMT. Our main focus is on TyrRS, because of the established reagents and knowledge necessary for exploration in a mammalian system and because of the recent evidence from a Drosophila model for the involvement of nuclear TyrRS in CMT. Although the main focus is on TyrRS, we will probe commonality with other subtypes of peripheral neuropathy as well as other neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. This is because the nuclear function of TyrRS is likely to be generally related to oxidative stress and to other important pathways and gene regulators that are relevant to the neurodegenerative process independent of CMT mutations.

抽象的 Charcot-Marie-Tooth（CMT）疾病，也称为遗传性运动和感觉神经病（HMSN）是 遗传性周围神经病的最常见形式，估计患病率为2500人，有1人 在美国约有大约125,000人。 CMT在长度上影响周围神经 依赖方式，其特征是无力和浪费远端的肢体肌肉导致 进行性运动障碍，感觉丧失和骨骼畸形。 CMT患者没有治疗。 CMT中实施的最大基因家族编码氨基酰基-TRNA合酶（AARSS），这是必不可少的 催化蛋白质生物合成中第一反应的酶，即转移RNA（TRNA）的充电（TRNA） 与它们的同源氨基酸。但是，了解CMT和AARSS之间的联系是一个挑战。 因为AARS是蛋白质合成中必不可少的参与者，因此据信tRNA中的CMT引起的突变 合成酶必须以某种方式影响蛋白质合成。奇怪的是，引起CMT的突变不一定是 影响酶的氨基化功能；几乎所有cmt-的tRNA合成酶突变 相关具有常染色体显性遗传，表明有功能的疾病机制。最后，如 蛋白质合成对于所有组织类型都是必不可少的，与CMT相关的非常组织特异性 表型使对AARS在CMT疾病中的作用的生物学理解变得复杂。有趣的是， 在真核细胞的核中也检测到胞质AARS。最初的假设是AARSS 在校对新特征的TRNA中的功能，后来的发现表明核局部AARSS 参与调节广泛的生物学过程，包括血管发展，创新， 压力反应主要是由于它们与转录机械相互作用的独特能力。 但是，核pyrrs的生物学功能从未在哺乳动物系统中的体内进行研究。 该项目的目的是探索核中AARS的物理功能及其与其与之的关系 CMT。我们的主要重点是Tyrrs，因为探索所必需的既定试剂和知识 在哺乳动物系统中，由于果蝇模型的最新证据表明 CMT中的核pyrrs。尽管主要重点是Tyrrs，但我们将与其他子类型进行探测 周围神经病以及其他神经退行性疾病，例如阿尔茨海默氏病，帕金森氏病 疾病，亨廷顿病和肌萎缩性侧索硬化症。这是因为Tyrr的核功能 通常可能与氧化应激以及其他重要途径和基因调节剂有关 与CMT突变无关的神经退行性过程有关。