The role of G3BP1 in mutant SOD1-mediated familial ALS

摘要 肌萎缩性侧索硬化症，也称为Lou Gehrig病或ALS，是一种进行性和致命的疾病， 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 由于运动神经元丧失而引起的肌肉萎缩。在家族性肌萎缩侧索硬化症中， 突变。第一个基因的突变被确定为导致ALS编码铜/锌超氧化物 SOD 1.目前还不完全清楚SOD 1突变如何导致ALS的毒性。其他几 突变导致ALS的基因编码RNA代谢调节剂，其已知功能似乎是 与SOD 1无关。这两种致病途径在ALS中的融合仍不清楚。 已知Ras GTP酶激活蛋白结合蛋白G3 BP 1调节细胞的稳定性， 信使RNA的翻译。它也是应激颗粒动力学的关键调节剂。应力颗粒形成 以应对氧化应激和热休克等挑战。应激颗粒暂时隔离 可有可无的信使RNA处于翻译失活形式，释放核糖体用于翻译 在压力下生存所必需的转录本。 SOD 1的ALS突变体形成细胞质内含物。我们发现突变的SOD 1包涵体 含有G3 BP 1。我们还发现突变体SOD 1和G3 BP 1之间存在RNA非依赖性相互作用。我们 假设是G3 BP 1代表了SOD 1中ALS突变与ALS之间的关键联系， RNA代谢的病理改变。 资助提案的目标1将确定ALS突变体SOD 1-G3 BP 1的分子细节 在细胞培养和体外模型中的相互作用。目的2将确定SOD 1的ALS突变体对胁迫的影响 细胞培养物和转基因小鼠模型中的颗粒动力学和G3 BP 1 RNA结合。目标3将测试 G3 BP 1和果蝇G3 BP 1同源物Rasputin/Rin在转基因人SOD 1毒性中的作用 飞行模型这些发现有望为SOD 1突变的机制提供重要的见解。 引起毒性和干扰RNA代谢。

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.