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.

作为社会代价最高的疾病之一，随着人口老龄化，神经退行性疾病的患病率不断上升然而，可供治疗的选择很少，并且在没有充分阐明病理机制的情况下，一个人产生干预理由的能力是我们的研究有望通过建立新的病因和方法来解决这一障碍。哺乳动物神经变性的分子机制之一是核糖体相关。质量控制 (RQC)，介导核糖体产生的不完整多肽的降解， RQC 中起作用的关键因素是 Ltn1/Listerin E3 泛素连接酶及其伙伴， NEMF（酵母中的 Rqc2）。PI Joazeiro 此前发现 Ltn1 突变会导致小鼠神经退行性变。 PI Cox 最近在小鼠 Nemf 中发现了两种导致运动神经元疾病的独立突变并利用这些知识来识别以前未确诊的具有类似神经肌肉疾病的患者 Ltn1-ENU 和 Nemf-ENU 小鼠以多种方式遗传了人类 NEMF 基因的致病突变。表型相互复制，从而加强了 RQC 功能障碍与神经退行性变之间的联系。拟议的研究旨在了解神经退行性变的分子机制我们的分析重点是最近发现的 NEMF 活性。从细菌到人类都是保守的——用C端丙氨酸尾修饰异常的新生链根据我们的初步数据，我们捕获了 NEMF 介导的 Ala 尾部。保护神经元免受退化。这些研究的结果有望提供重要的理解。蛋白质质量控制缺陷如何导致神经系统疾病。