Polyalanine Tails: A Novel Type of Protein Modification Implicated in Neurodegeneration

聚丙氨酸尾：一种与神经变性有关的新型蛋白质修饰

基本信息

批准号：
10521560
负责人：
GREGORY A. COX
金额：
$ 75.12万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521560
关键词：
Address Alanine Amyotrophic Lateral Sclerosis Bacteria Basic Science Behavioral Binding Biochemical Biological Assay Biology C-terminal Cell model Cells Complex Data Defect Development Disease Ethylnitrosourea Etiology Exhibits Functional disorder Funding Genes Goals Histopathology Human Induced Mutation Inherited Intervention Investigation Knowledge Lead Light Mammalian Cell Mediating Modeling Modification Molecular Motor Motor Neuron Disease Motor Neurons Mouse Strains Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuromuscular Diseases Neuromuscular conditions Neurons Nitrosourea Compounds Nuclear Export Orthologous Gene Paralysed Patients Phenocopy Phenotype Play Post-Translational Protein Processing Prevalence Proteins Proteolysis Public Health Quality Control Reporting Research Research Proposals Ribosomes Role Societies Spinal Cord System Tail Testing Tissues Toxic effect Translations Variant Work Yeasts aging population base causal variant cofactor cytotoxicity design early onset fitness human disease insight loss of function mouse model mutant nervous system disorder neurodegenerative phenotype novel novel therapeutics polyalanine polypeptide protein aggregation sporadic amyotrophic lateral sclerosis therapeutically effective ubiquitin-protein ligase

项目摘要

Among the costliest diseases to society, and with rising prevalence in an aging population, neurodegenerative diseases pose a public health challenge. However, there are few options available for their treatment, and without pathomechanisms being sufficiently elucidated, one's ability to generate a rationale for interventions is greatly limited. Our studies are expected to address this barrier by establishing new etiological factors and molecular mechanisms of mammalian neurodegeneration. One such mechanism is Ribosome-associated Quality Control (RQC), that mediates the degradation of incomplete polypeptides produced by ribosomes that stall during translation. Key factors working in RQC are the Ltn1/Listerin E3 ubiquitin ligase and its partner, NEMF (Rqc2 in yeast). PI Joazeiro has previously found that Ltn1 mutation causes neurodegeneration in mice. PI Cox has more recently identified two independent mutations in mouse Nemf causing motor neuron disease and used this to knowledge to identify previously undiagnosed patients with a similar neuromuscular condition that inherited causative mutations in the human NEMF gene. In several ways, Ltn1-ENU and Nemf-ENU mice phenocopy each other, thus strengthening the connection between RQC dysfunction and neurodegeneration. The proposed studies are aimed at understanding molecular mechanisms underlying neurodegeneration caused by NEMF loss of function. We focus our analyses on a recently-discovered activity of NEMF that is conserved from bacteria to humans–the modification of aberrant nascent chains with C-terminal Alanine tails that have a proteolytic function. Based on our preliminary data, we hypothesize that NEMF-mediated Ala tailing protects neurons against degeneration. Results of these studies are expected to provide critical understanding of how defects in protein quality control lead to neurological disease.

在社会最昂贵的疾病中，在老龄化的人群中，神经退行性的疾病越来越上升。疾病构成公共卫生挑战。但是，很少有选择可以治疗，并且如果没有足够的病理机理，就可以为干预措施产生理由的能力是非常有限。我们的研究有望通过建立新的病因因素和哺乳动物神经退行性的分子机制。一种这样的机制是核糖体相关质量控制（RQC），介导核糖体产生的不完整多肽的降解翻译过程中的失速。在RQC中起作用的关键因素是LTN1/李斯特蛋白E3泛素连接酶及其伴侣， NEMF（酵母中的RQC2）。 Pi Joazeiro以前已经发现LTN1突变会导致小鼠的神经退行性。 Pi Cox最近发现了小鼠NEMF中引起运动神经元疾病的两个独立突变并以此为识别具有相似神经肌肉疾病的先前未诊断的患者遗传了人类NEMF基因中的因果突变。 LTN1-ENU和NEMF-ENU小鼠在几种方面彼此的表情，从而增强了RQC功能障碍与神经退行性之间的联系。拟议的研究旨在理解神经退行性的分子机制由NEMF的功能丧失引起。我们将分析重点放在NEMF最近发现的活动上从细菌到人的保守 - 与C末端丙氨酸尾巴的异常新生链的修饰具有蛋白水解功能。根据我们的初步数据，我们假设NEMF介导的Ala尾巴保护神经元免受变性。这些研究的结果有望提供批判性的理解蛋白质质量控制缺陷如何导致神经系统疾病。