CAT-tails: A Novel Type of Protein Modification Implicated in Neurodegeneration

CAT-tails：一种与神经退行性疾病有关的新型蛋白质修饰

基本信息

批准号：
9910468
负责人：
GREGORY A. COX
金额：
$ 66.24万
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 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910468
关键词：
ALS patients Address Affect Amyloid Amyotrophic Lateral Sclerosis Basic Science Behavioral Biochemical Bioinformatics Biological Models C-terminal Complex Cryoelectron Microscopy Data Defect Detergents Development Disease Ethylnitrosourea Etiology Exhibits Functional disorder Genes Genetic Polymorphism Genetic Structures Goals Human Knowledge Lead Link Mammals Mediating Modification Molecular Molecular Genetics Motor Neuron Disease Motor Neurons Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurologic Neurons Nitrosourea Compounds Nuclear Export Orthologous Gene Paralysed Pathway interactions Patients Phenotype Play Post-Translational Protein Processing Prevalence Proteins Public Health Quality Control Reporting Research Proposals Resistance Resources Ribosomes Role Spinal Cord Structure Tail Testing Toxic effect Translations Treatment Efficacy Ubiquitination Variant Work Yeast Model System Yeasts base biochemical model early onset human disease insight member motor neuron degeneration mouse model mutant nervous system disorder neurodegenerative phenotype novel novel therapeutics polypeptide response tissue culture ubiquitin-protein ligase

项目摘要

We have identified two independent ENU-induced mouse mutations in the nuclear export mediating factor (Nemf) causing a motor neuron disease with many phenotypic hallmarks of amyotrophic lateral sclerosis (ALS). NEMF has recently been shown to be a key component of the stalled-ribosome quality control complex (RQC) that allows for ubiquitination, C-terminal addition of poly Ala/Thr tails (CAT-tails) and disposal of ribosome-stalled nascent polypeptide chains. Co-PI Joazeiro has previously characterized a mouse model of neurodegeneration caused by ENU mutation of another RQC complex member, Listerin (Ltn1). In several ways, the Ltn1-ENU phenotype resembles that of other mouse models of ALS including the newly discovered Nemf mouse models, thus solidifying the connection between RQC dysfunction and neurodegeneration. Preliminary work has identified human sporadic ALS patients with rare and potentially damaging NEMF polymorphisms. Thus, the identification of the novel NEMF mouse model provides a key resource for determining how defects in protein quality control mechanisms may lead to neurological disease. We hypothesize that misregulated ribosomal quality control can underlie motor neuron disease, and that NEMF is a putative new ALS-associated disease gene critical for regulating normal neuronal function. !

我们已经确定了两个独立的ENU诱导的小鼠突变在核输出介导因子中（NEMF）引起运动神经元疾病，具有许多肌萎缩性侧索硬化症的表型标志（ALS）。 NEMF最近被证明是停滞的 - 核糖体质量控制复合物的关键组成部分（RQC）允许泛素化，c末端添加聚Ala/thr尾巴（猫尾）和处置核糖体恒定的新生多肽链。 Co-Pi Joazeiro以前已经表征了一个小鼠模型神经变性是由另一个RQC复合成员李斯特蛋白（LTN1）的ENU突变引起的。在几个方式，LTN1-ENU表型类似于其他鼠标的ALS模型，包括新发现的 NEMF小鼠模型，从而巩固了RQC功能障碍与神经变性之间的连接。初步工作已经确定了人类零星的ALS患者，患有罕见且可能破坏的NEMF 多态性。因此，新型NEMF鼠标模型的识别为确定蛋白质质量控制机制中缺陷如何导致神经疾病。我们假设核糖体质量控制不道德的可能是运动神经元疾病的基础，而NEMF是推定的新型ALS相关疾病基因对于调节正常神经元功能至关重要。呢