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

C9ORF72 蛋白功能在肌萎缩侧索硬化症和额颞叶痴呆中的作用

• 批准号: 9484651
• 负责人: Justin Kawika Ichida
• 金额: $ 1.29万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9484651
• 关键词: Accounting; Amyotrophic Lateral Sclerosis; Biogenesis; C9ORF72; CRISPR/Cas technology; Dipeptides; Disease model; Frontotemporal Dementia; Genetic; Genetic Transcription; Glutamate Receptor; Glutamates; Goals; Guanine; Guanine Nucleotide Exchange Factors; Human; Hypersensitivity; Lead; Mediating; Modernization; Motor Neurons; Mutation; Nerve Degeneration; Nervous system structure; Neurons; Northern Europe; Nuclear RNA; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Process; Production; Protein Isoforms; Proteins; Research; Role; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Translating; Work; excitotoxicity; gain of function; genome editing; inhibitor/antagonist; kinase inhibitor; knock-down; motor neuron function; mutant; neurotoxic; prevent; protein function; rab GTP-Binding Proteins; small molecule; targeted treatment; therapeutic development; therapeutic target; trafficking

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.

项目概要/摘要 C9ORF72 重复扩增突变是肌萎缩侧索硬化症 (ALS) 的最常见原因 和额颞叶痴呆 (FTD)，占北欧 ALS 病例的 50% 以上，占欧洲国家 ALS 病例的 10% 世界范围内的病例，使其成为治疗干预的关键目标。该病的致病机制 C9ORF72 重复扩展尚不清楚，是本提案的重点，因为它的阐明对于 治疗的发展。研究表明，重复扩增会产生神经毒性物质，包括 二肽重复蛋白和核 RNA 焦点已将该领域的治疗重点转向阻断 这些产品的毒性。然而，我们的初步研究使用患者特异性诱导运动神经元 由细胞重编程产生的（iMN）和主要患者组织分析表明，C9ORF72 RAB GTPases 的鸟嘌呤交换因子活性介导早期内体运输和溶酶体 生物发生。此外，他们表明这种活性的单倍体不足会导致神经变性。这 这项研究的目标是明确表明鸟嘌呤交换因子活性的单倍体不足会导致 C9ORF72 ALS/FTD 中的神经退行性疾病通过以下具体目标：(1) 识别神经退行性变 由低 C9ORF72 蛋白水平引起的过程，(2) 确定 C9ORF72 的功能，(3) 确定是否 PIKFYVE 抑制通过拯救内体运输来促进 iMN 存活。该应用程序旨在改变 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 中的神经变性。拟议的研究将建立 C9ORF72 蛋白活性作为 关键的治疗目标。更广泛地说，我们的工作将强调内体的机械趋同 ALS 和 FTD 的贩运，确定了对大部分 ALS/FTD 具有治疗潜力的途径 患者。