The Role of C9ORF72 Protein Function in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

项目摘要/摘要 C9ORF72重复扩增突变是肌萎缩侧索硬化症(ALS)最常见的原因 额颞叶痴呆(FTD)，占北欧ALS病例的50%以上，占10% 全世界的病例，使其成为治疗干预的重要目标。黄褐斑的致病机制 C9ORF72重复扩增尚不清楚，是这项提案的重点，因为它的阐明对 治疗方面的发展。研究表明，重复扩张会产生神经毒性物质，包括 二肽重复蛋白和核糖核糖核酸的焦点已经将治疗的重点转向了阻断 这些产品的毒性。然而，我们的初步研究使用了患者特定的诱导运动神经元 (IMN)由细胞重新编程产生，和原发患者组织分析表明，C9ORF72有 介导早期内体转运和溶酶体的RAB GTP酶的鸟嘌呤交换因子活性 生物发生学。此外，他们还指出，这种活动的单倍体不足会导致神经退化。这个 这项研究的目的是明确地表明，鸟嘌呤交换因子活性的单倍体不足会导致 C9ORF72 ALS/FTD的神经退行性变通过以下特定目的：(1)鉴定神经退行性变 由低水平的C9ORF72蛋白引起的过程，(2)确定C9ORF72的功能，(3)确定是否 PIKfyve抑制通过挽救内体运输促进IMN存活。此应用程序试图转移 目前的研究表明，鸟嘌呤交换因子活性的单倍体不足会导致 C9ORF72 ALS/FTD的神经退行性变拟议的研究将确定C9ORF72蛋白的活性是一种 关键的治疗目标。更广泛地说，我们的工作将突出内涵体的机械性趋同。 ALS和FTD的贩运，确定对大部分ALS/FTD具有治疗潜力的途径 病人。

Project Summary/Abstract The C9ORF72 repeat expansion mutation is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), accounting for over 50% of ALS cases in northern Europe and 10% of cases worldwide, making it a critical target for therapeutic intervention. The pathogenic mechanism of the C9ORF72 repeat expansion is unclear and is the focus of this proposal because its elucidation is crucial for therapeutic development. Studies showing that the repeat expansion generates neurotoxic species including dipeptide repeat proteins and nuclear RNA foci have oriented the field towards a therapeutic focus on blocking the toxicity of these products. However, our preliminary studies using patient-specific induced motor neurons (iMNs) generated by cellular reprogramming, and primary patient tissue analysis, suggest that C9ORF72 has guanine exchange factor activity for RAB GTPases that mediate early endosomal trafficking and lysosomal biogenesis. Moreover, they indicate that haploinsufficiency for this activity leads to neurodegeneration. The goal of this study is to definitively show that haploinsufficiency for guanine exchange factor activity leads to neurodegeneration in C9ORF72 ALS/FTD through the following specific aims: (1) Identify neurodegenerative processes caused by low C9ORF72 protein levels, (2) Determine the function of C9ORF72, (3) Determine if PIKFYVE inhibition promotes iMN survival by rescuing endosomal trafficking. This application seeks to shift current research by demonstrating that haploinsufficiency for guanine exchange factor activity induces neurodegeneration in C9ORF72 ALS/FTD. The proposed study will establish C9ORF72 protein activity as a critical therapeutic target. More broadly, our work will highlight a mechanistic convergence on endosomal trafficking in ALS and FTD, identifying a pathway with therapeutic potential for a large percentage of ALS/FTD patients.