RAD23 Control of ALS phenotypes

RAD23 对 ALS 表型的控制

基本信息

批准号：
10617853
负责人：
Robert G Kalb
金额：
$ 40万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617853
关键词：
ALS patients Ablation Acceleration Amyotrophic Lateral Sclerosis Antisense Oligonucleotides Autophagocytosis Behavior Biochemical Biochemistry Biological Models Caenorhabditis elegans Cell physiology Cells Clinical Degradation Pathway Disease Disease Progression Equilibrium Genes Genetic Goals Health Health Promotion Histology Image Impairment In Vitro MG132 Mammals Mediating Modeling Mus Mutate Nematoda Neurodegenerative Disorders Organism Pathway interactions Phenotype Play Process Proteasome Inhibition Protein Biosynthesis Protein Isoforms Proteins RAD23B gene Role System Technology Testing Therapeutic Transgenic Mice Translating Ubiquitin Work Yeasts experimental study improved inhibitor innovation knock-down misfolded protein mouse model multicatalytic endopeptidase complex mutant operation polyglutamine protein TDP-43 protein aggregation protein degradation proteostasis tissue culture translational potential ultraviolet irradiation

项目摘要

Abstract The accumulation of damaged, misfolded and aggregation-prone proteins in neurodegenerative diseases reflects corruption of cellular protein homeostasis (or “proteostasis”). Proteostasis is the proper balance of protein synthesis and protein degradation that is required for optimal cellular functioning. The identification of misfolded proteins and their targeting to the major degradative pathways (i.e., the proteasome or the autophagy pathway) are highly regulated processes. A key protein in this process is RAD23. RAD23 promotes the degradation of some proteins and stabilizes cellular levels of other proteins. The mechanism underlying these diametrically opposed operations is not understood. Interestingly, ablation of rad23 accelerates the destruction several disease-causing, aggregation-prone mutated proteins (i.e., polyQ expanded Ataxin3, TDP43, SOD) and confers benefits in a variety of model systems. We hypothesize that RAD23 bridges ubiquitinated misfolded proteins with the proteasome and in doing so, sterically or allosterically inhibits proteasome function. In this way, RAD23 impairs proteostasis. In specific aim #1, we will use imaging and biochemical approaches to test this mechanism of RAD23 action. In in vitro and C.elegans models of ALS, loss of RAD23 is health promoting – whether this is true in mouse models is unknown. Mammals have 2 rad23 isoforms, rad23A and rad23B. In specific aims 2-4, we will use genetic and anti-sense oligomer technology to ablate and/or knockdown rad23A, rad23B or both in several mouse models of ALS. We will comprehensively interrogate the effects of loss of rad23A/B on mouse survival, behavior and biochemistry. The successful completion of these studies has the potential to be translated into clinical therapeutics.

抽象的受损、错误折叠和易于聚集的蛋白质的积累神经退行性疾病反映了细胞蛋白质稳态的破坏（或 “蛋白质稳态”）。蛋白质稳态是蛋白质合成和蛋白质降解的适当平衡。这是最佳细胞功能所必需的。针对主要降解途径（即蛋白酶体或自噬途径） RAD23 是受到高度调控的过程。降解一些蛋白质并稳定其他蛋白质的细胞水平。这些截然相反的操作背后的原因尚不清楚。 rad23 加速破坏几种致病、易聚集的突变蛋白（即，polyQ 扩展了 Ataxin3、TDP43、SOD）并在多种模型中带来益处我们认为 RAD23 将泛素化的错误折叠蛋白与蛋白酶体，并以此方式空间或变构地抑制蛋白酶体功能。 RAD23 损害蛋白质稳态在具体目标 1 中，我们将使用成像和生化。测试 RAD23 作用机制的体外和线虫 ALS 模型。 RAD23 的缺失有利于健康——这在小鼠模型中是否属实尚不清楚。哺乳动物有 2 种 rad23 同工型：rad23A 和 rad23B 在具体目标 2-4 中，我们将使用遗传。和反义寡聚物技术，以消除和/或敲低 rad23A、rad23B 或两者我们将全面研究几种 ALS 小鼠模型。 rad23A/B 对小鼠生存、行为和生物化学的影响成功完成这些。研究有可能转化为临床治疗。