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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：
10626155
负责人：
Robert W Burgess
金额：
$ 73.22万
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/10626155
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 neuroprotection 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.

神经退行性疾病是社会代价最高的疾病之一，随着人口老龄化，疾病对公共卫生构成挑战。然而，他们的治疗方法很少，如果没有充分阐明病理机制，人们产生干预理由的能力是非常有限。我们的研究预计将通过建立新的病因因素来解决这一障碍，哺乳动物神经退化的分子机制。其中一种机制是核糖体相关的质量控制（RQC），介导核糖体产生的不完整多肽的降解，在翻译过程中停顿。在RQC中起作用的关键因素是Ltn 1/Listerin E3泛素连接酶及其伴侣， NEMF（酵母中的Rqc 2）。PI Joazhoun先前发现Ltn 1突变导致小鼠神经退行性变。 PI考克斯最近发现了两个独立的突变，在小鼠Nemf引起运动神经元疾病并利用这一知识来识别以前未确诊的类似神经肌肉疾病的患者遗传了人类NEMF基因的致病突变。在几个方面，Ltn 1-ENU和Nemf-ENU小鼠表型相互模仿，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变性的分子机制是由NEMF功能丧失引起的。我们把我们的分析集中在最近发现的NEMF活动上，从细菌到人类的保守性-C-末端丙氨酸尾对异常新生链的修饰具有蛋白水解功能。基于我们的初步数据，我们假设NEMF介导的Ala拖尾保护神经元免于退化。这些研究的结果预计将提供关键的理解蛋白质质量控制的缺陷如何导致神经系统疾病。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10.

DOI：
10.1016/j.celrep.2023.113100
发表时间：
2023-09-26
期刊：
Cell reports
影响因子：
8.8
作者：
通讯作者：

Ribosome-associated quality-control mechanisms from bacteria to humans.

DOI：
10.1016/j.molcel.2022.03.038
发表时间：
2022-04-21
期刊：
MOLECULAR CELL
影响因子：
16
作者：
Filbeck, Sebastian;Cerullo, Federico;Pfeffer, Stefan;Joazeiro, Claudio A. P.
通讯作者：
Joazeiro, Claudio A. P.

Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing.

DOI：
10.1016/j.molcel.2021.03.004
发表时间：
2021-05-20
期刊：
Molecular cell
影响因子：
16
作者：
Thrun A;Garzia A;Kigoshi-Tansho Y;Patil PR;Umbaugh CS;Dallinger T;Liu J;Kreger S;Patrizi A;Cox GA;Tuschl T;Joazeiro CAP
通讯作者：
Joazeiro CAP

Identification of quantitative trait loci for survival in the mutant dynactin p150Glued mouse model of motor neuron disease.

DOI：
10.1371/journal.pone.0274615
发表时间：
2022
期刊：
PloS one
影响因子：
3.7
作者：
通讯作者：

A microfluidic approach to rescue ALS motor neuron degeneration using rapamycin.

DOI：
10.1038/s41598-021-97405-1
发表时间：
2021-09-13
期刊：
Scientific reports
影响因子：
4.6
作者：
Chennampally P;Sayed-Zahid A;Soundararajan P;Sharp J;Cox GA;Collins SD;Smith RL
通讯作者：
Smith RL