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

• 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
• 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

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.

在社会代价最高的疾病中，随着老龄化人口患病率的上升，神经退行性疾病 疾病对公共卫生构成了挑战。然而，治疗他们的选择很少，而且 在没有充分阐明发病机制的情况下，一个人产生干预的理由的能力是 非常有限。我们的研究有望通过建立新的病因和 哺乳动物神经退变的分子机制。一种这样的机制是核糖体相关的 质量控制(RQC)，调节核糖体产生的不完全多肽的降解 在转换过程中停顿。在RQC中起作用的关键因素是Ltn1/Listerin E3泛素连接酶及其合作伙伴， NEMF(酵母中的Rqc2)。Pi Joazeiro此前曾发现，Ltn1突变会导致小鼠的神经退化。 皮考克斯最近在导致运动神经元疾病的小鼠NEMF中发现了两个独立的突变 并利用这一知识来识别之前未被诊断出有类似神经肌肉疾病的患者 它遗传了人类NEMF基因的致病突变。在几个方面，Ltn1-enu和Nemf-enu小鼠 表型相互复制，从而加强RQC功能障碍和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。 由NEMF功能丧失所致。我们的分析集中在最近发现的NEMF活动上，即 从细菌到人类的保守性-C-末端丙氨酸尾巴对异常新生链条的修饰 具有蛋白质分解功能的物质。根据我们的初步数据，我们假设NEMF介导的ALA拖尾 保护神经元免受退化。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疾病。