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: 10598557
• 负责人: Robert W Burgess
• 金额: $ 54.22万
• 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/10598557
• 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; Curiosities; Data; Deformity; Development; Disease; Distal; Drosophila genus; Engineering; Enzymes; Equation; Eukaryotic Cell; Gene Family; Genetic Transcription; Goals; HDAC1 gene; Hereditary Motor and Sensory Neuropathies; Heterozygote; Hindlimb; Homozygote; Huntington Disease; Inflammation; Inherited; Knock-in; Knowledge; 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; autosome; 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 腓骨肌萎缩症 (CMT) 病，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 2500 人中有 1 人， 相当于美国约 125,000 人。 CMT 长期影响周围神经 依赖方式，其特征是远端肢体肌肉无力和萎缩，导致 进行性运动障碍、感觉丧失和骨骼畸形。 CMT 患者没有可用的治疗方法。 与 CMT 相关的最大基因家族编码氨酰基-tRNA 合成酶 (aaRS)，这是必需的 催化蛋白质生物合成第一个反应的酶，即转移 RNA (tRNA) 的充电 及其同源氨基酸。然而，理解 CMT 和 aaRS 之间的联系是一个挑战。 由于 aaRS 在蛋白质合成中发挥重要作用，因此认为引起 CMT 的 tRNA 突变 合成酶必定以某种方式影响蛋白质合成。奇怪的是，引起 CMT 的突变并不一定 影响酶的氨酰化功能；几乎所有 tRNA 合成酶突变都是 CMT- 相关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 蛋白质合成对于所有组织类型都是必需的，与 CMT 相关的极端组织特异性 表型使得对 aaRS 在 CMT 疾病中的作用的生物学理解变得复杂。有趣的是， 在真核细胞的细胞核中也检测到胞质 aaRS。虽然最初的假设是 aaRS 此处的功能是校对新合成的 tRNA，后来的研究结果表明核定位的 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。 该项目的目标是探索细胞核中aaRS的生理功能及其与细胞核的关系。 CMT。我们的主要关注点是 TyrRS，因为其拥有探索所需的既定试剂和知识 在哺乳动物系统中，并且由于最近来自果蝇模型的证据表明参与 CMT 中的核 TyrRS。尽管主要关注的是 TyrRS，但我们将探讨与其他亚型的共性 周围神经病变以及其他神经退行性疾病，如阿尔茨海默病、帕金森病 病、亨廷顿病和肌萎缩侧索硬化症。这是因为 TyrRS 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因子有关 与独立于 CMT 突变的神经退行性过程相关。