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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. !

我们已经鉴定出两种独立的 ENU 诱导的小鼠核输出介导因子突变 (Nemf) 引起运动神经元疾病，具有肌萎缩侧索硬化症的许多表型特征（肌萎缩侧索硬化症）。 NEMF 最近被证明是停滞核糖体质量控制复合体的关键组成部分 (RQC)，允许泛素化、C 端添加聚丙氨酸/苏氨酸尾 (CAT-尾) 和处理核糖体停滞的新生多肽链。联合首席研究员 Joazeiro 此前曾对小鼠模型进行过表征由另一个 RQC 复合体成员李施德林 (Ltn1) 的 ENU 突变引起的神经退行性变。在几个 Ltn1-ENU 表型与其他 ALS 小鼠模型相似，包括新发现的 Nemf 小鼠模型，从而巩固了 RQC 功能障碍与神经退行性疾病之间的联系。初步工作已确定人类散发性 ALS 患者患有罕见且具有潜在破坏性的 NEMF 多态性。因此，新型 NEMF 小鼠模型的鉴定为确定蛋白质质量控制机制的缺陷如何导致神经系统疾病。我们假设核糖体质量控制失调可能是运动神经元疾病的基础，并且 NEMF 是一种推定的新的 ALS 相关疾病基因，对于调节正常神经元功能至关重要。！