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: 10380653
• 负责人: Robert W Burgess
• 金额: $ 53.42万
• 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: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380653
• 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; Persons; 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.

摘要 腓骨肌萎缩症（CMT），也称为遗传性运动和感觉神经病（HMSN），是一种 最常见的遗传性周围神经病，估计患病率为1/2500， 相当于美国约125，000人。CMT影响周围神经的长度- 依赖的方式，其特征在于远端肢体肌肉的虚弱和消耗， 进行性运动障碍、感觉丧失和骨骼畸形。CMT患者无可用治疗。 与CMT有关的最大基因家族编码氨酰-tRNA合成酶（aaRSs），其是必需的。 催化蛋白质生物合成中第一个反应的酶，即转运RNA（tRNA）的充电 与它们的同源氨基酸。然而，理解CMT和aaRS之间的联系是一个挑战。 由于aaRS是蛋白质合成的重要参与者，因此认为tRNA中引起CMT的突变 合成酶一定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 影响酶的氨酰化功能;几乎所有的tRNA合成酶突变都是CMT- 相关的具有常染色体显性遗传，提示功能获得性疾病机制。最后，作为 蛋白质合成对所有组织类型都是必需的，与CMT相关的极端组织特异性 表型使aaRS在CMT疾病中的作用的生物学理解复杂化。有趣的是， 在真核细胞的细胞核中也检测到胞质aaRS。虽然最初的假设是aaRS 在校正新合成的tRNA中起作用，后来的发现表明，核定位的aaRS 参与调节广泛的生物过程，包括血管发育，炎症， 和应激反应主要是由于它们与转录机制相互作用的独特能力。 然而，核TyrRS的生物学功能从未在哺乳动物系统中进行过体内研究。 本研究的目的是探讨核内aaRSs的生理功能及其与细胞凋亡的关系。 CMT。我们的主要重点是TyrRS，因为已经建立了探索所需的试剂和知识 在哺乳动物系统中，由于最近来自果蝇模型的证据表明， CMT中的核TyrRS。虽然主要的焦点是TyrRS，我们将探讨与其他亚型的共性。 周围神经病以及其他神经退行性疾病如阿尔茨海默病、帕金森病、 疾病、亨廷顿病和肌萎缩侧索硬化症。这是因为TyrRS的核功能 很可能与氧化应激和其他重要的途径和基因调节因子有关， 与CMT突变无关的神经退行性过程相关。