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The role of G3BP1 in mutant SOD1-mediated familial ALS

G3BP1 在突变型 SOD1 介导的家族性 ALS 中的作用

基本信息

批准号：
9332487
负责人：
Jozsef Gal
金额：
$ 18.81万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332487
关键词：
ALS patients Address Amyotrophic Lateral Sclerosis Appearance Applications Grants Binding Proteins Biological Models Cell Culture Techniques Co-Immunoprecipitations Collaborations Cuprozinc Superoxide Dismutase Cytoplasmic Granules Cytoplasmic Inclusion Data Defect Disease Drosophila genus Etiology Future G3BP1 gene Gene Mutation Genes Genetic Heat-Shock Response Homologous Gene Human Immunoprecipitation In Vitro Inherited Link Mediating Messenger RNA Metabolism Modeling Molecular Motor Neurons Muscle Weakness Muscular Atrophy Mutagenesis Mutate Mutation Neurodegenerative Disorders Outcome Oxidative Stress Oxides Pathogenesis Pathogenicity Pathologic Pathway interactions Phenotype Play Preventive measure Proteins RNA RNA Binding Reagent Reporting Research Resolution Ribonucleosides Ribosomes Role SCA2 protein Sampling Spinal Cord Stress Surface Symptoms Testing Time Toxic effect Transcript Transgenic Mice Transgenic Organisms Translations base crosslink design experimental study fly in vitro Model in vivo insight matrin 3 motor neuron degeneration mouse model mutant neuron loss novel overexpression protein TDP-43 ras GTPase-Activating Proteins response superoxide dismutase 1

项目摘要

Abstract Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease or ALS is a progressive and fatal neurodegenerative disease with no cure available. In order to develop effective preventive measures or cures, we have to gain a better understanding of the molecular pathogenesis of ALS. A general symptom of ALS is muscle wasting caused by motor neuron loss. In familial ALS, the disease is caused by inherited gene mutations. The first gene whose mutations were identified to cause ALS encodes the Cu/Zn superoxide dismutase SOD1. It is still not fully understood how the mutations in SOD1 cause toxicity in ALS. Several other genes whose mutations cause ALS encode RNA metabolism regulators whose known functions are seemingly unrelated to that of SOD1. The convergence of these two pathogenic pathways in ALS is still unclear. The Ras GTPase-activating protein-binding protein G3BP1 is known to regulate the stability and translation of messenger RNAs. It is also a critical regulator of stress granule dynamics. Stress granules form in response to challenges such as oxidative stress and heat shock. Stress granules sequester temporarily dispensable messenger RNAs in translationally inactive form, freeing up ribosomes for the translation of transcripts that are essential to survive the stress. ALS mutants of SOD1 form cytoplasmic inclusions. We found that the mutant SOD1 inclusions contained G3BP1. We also found an RNA independent interaction between mutant SOD1 and G3BP1. Our hypothesis is that G3BP1 represents a critical link between the ALS mutations in SOD1 and the pathological alterations in RNA metabolism. Aim 1 of the grant proposal will determine the molecular details of the ALS mutant SOD1-G3BP1 interaction in cell culture and in vitro models. Aim 2 will determine the effect of ALS mutants of SOD1 on stress granule dynamics and G3BP1 RNA binding in cell culture and transgenic mouse models. Aim 3 will test the role of G3BP1 and the Drosophila G3BP1 homolog Rasputin/Rin in the toxicity of transgenic human SOD1 in a fly model. The findings are expected to provide important insight into the mechanism by which SOD1 mutations cause toxicity and perturb RNA metabolism.

抽象的肌萎缩侧索硬化症，也称为卢伽雷氏病或 ALS，是一种进行性且致命的疾病无法治愈的神经退行性疾病。为了制定有效的预防措施或治疗方法，我们必须更好地了解 ALS 的分子发病机制。 ALS 的一般症状是运动神经元损失引起的肌肉萎缩。在家族性 ALS 中，该疾病是由遗传基因引起的突变。第一个被确定导致 ALS 突变的基因编码铜/锌超氧化物歧化酶SOD1。目前尚不完全清楚 SOD1 突变如何导致 ALS 毒性。其他几个导致 ALS 突变的基因编码 RNA 代谢调节因子，其已知功能似乎尚不明确。与SOD1无关。 ALS 中这两种致病途径的融合仍不清楚。 Ras GTP 酶激活蛋白结合蛋白 G3BP1 已知可调节稳定性和信使RNA的翻译。它也是应激颗粒动力学的关键调节剂。应力颗粒形式应对氧化应激和热休克等挑战。应力颗粒暂时隔离翻译非活性形式的可有可无的信使RNA，释放核糖体用于翻译应对压力所必需的转录本。 SOD1 的 ALS 突变体形成细胞质内含物。我们发现突变型 SOD1 内含物含有G3BP1。我们还发现突变体 SOD1 和 G3BP1 之间存在独立于 RNA 的相互作用。我们的假设 G3BP1 代表 SOD1 中的 ALS 突变与 RNA代谢的病理改变。拨款提案的目标 1 将确定 ALS 突变体 SOD1-G3BP1 的分子细节细胞培养和体外模型中的相互作用。目标 2 将确定 SOD1 的 ALS 突变体对应激的影响细胞培养和转基因小鼠模型中的颗粒动力学和 G3BP1 RNA 结合。目标 3 将测试 G3BP1 和果蝇 G3BP1 同源物 Rasputin/Rin 在转基因人 SOD1 毒性中的作用飞行模型。这些发现有望为 SOD1 突变的机制提供重要的见解引起毒性并干扰 RNA 代谢。