Exploring Mechanisms of Pathogenicity in C9ORF72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

项目摘要/摘要 与年龄相关的神经退行性疾病是社会的主要经济和情感负担，但到目前为止还没有 已经制定了预防策略。额颞性痴呆(FTD)和肌萎缩侧索硬化症(ALS)是 无情的进行性疾病，涉及对行为和肌肉运动至关重要的神经元退化， 分别进行了分析。C9ORF72基因非蛋白质编码区的六核苷酸重复扩增是最近被发现的 被发现是FTD和ALS最常见的原因，占所有诊断的10%。盛行的两个 已经提出了一些假设来解释这种突变是如何导致神经元的进行性丧失的。函数的增益 (GOF)假说提出，重复扩张产生的有毒分子扰乱神经功能，导致 他们的毁灭。功能丧失(LOF)假说认为C9ORF72蛋白在 支持神经功能和存活以及该基因表达减少直接或间接地使神经元对 疾病。新证据表明，C9ORF72小鼠同源基因在免疫系统中的作用有限 炎症和自身免疫，尽管确切的机制需要进一步研究。这项提案的第一个目标是 确定当C9ORF72同源基因减少时导致炎症的途径和细胞类型，并 检测C9ORF72重复序列是否能诱导人类多能干细胞来源的小胶质细胞样细胞 扩张表现出相似的炎症表型。这项建议的第二个目的是测试 通过将含有六核苷酸重复序列扩张的病毒注射到表达基因的小鼠体内，在活体中进行LOF假说 C9ORF72直系同源基因水平正常或降低。如果较低水平的C9ORF72同源基因使动物对有毒物质敏感 重复扩大的特点，这将为开发旨在提高水平的治疗提供支持 C9ORF72或受其还原影响的抑制通路。候选人将与不同领域的专家一起接受培训，以 培养完成这些目标所需的技术技能，并确定与疾病相关的途径 在本提案的独立阶段继续进行。与候选人的顾问和专家一起继续培训 合作者将为他成功实现他的目标做好准备，他将在其中指导一个独立的研究小组 所有级别的研究人员都在追寻假说，旨在了解神经退行性疾病的病因。

Project Summary/Abstract Age-related neurodegenerative disorders represent a major financial and emotional burden to society, but to date no preventative strategies have been developed. Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS) are relentlessly progressive diseases which involve the degeneration of neurons important for behavior and muscle movement, respectively. A hexanucleotide repeat expansion in a non-protein-coding region of the gene C9ORF72 was recently discovered to be the most common cause of FTD and ALS, responsible for 10% of all diagnoses. Two prevailing hypotheses have been suggested to explain how this mutation leads to progressive loss of neurons. The gain of function (GOF) hypothesis proposes that toxic molecules produced from the repeat expansion disrupt neural function and lead to their destruction. The loss of function (LOF) hypothesis proposes that the C9ORF72 protein plays an important role in support of neural function and survival and that reduced expression of this gene directly or indirectly sensitizes neurons to disease. New evidence indicates that the mouse ortholog of C9ORF72 functions in the immune system to limit inflammation and autoimmunity, although the exact mechanisms require further study. The first AIM of this proposal will be to identify pathways and cell types that contribute to inflammation when the C9ORF72 ortholog is reduced and to determine whether induced pluripotent stem cell-derived microglia-like cells from humans with the C9ORF72 repeat expansion display similar inflammatory phenotypes. The second AIM of this proposal seeks to test the validity of the LOF hypothesis in live organisms by injecting virus containing the hexanucleotide repeat expansion into mice that express normal or reduced levels of the C9ORF72 ortholog. If lower levels of the C9ORF72 ortholog sensitize animals to toxic features of the repeat expansion, this would provide support for developing therapies aimed at boosting levels of C9ORF72 or inhibiting pathways affected by its reduction. The candidate will train with experts in diverse fields to develop the technical skills necessary to complete these AIMs and to identify disease relevant pathways which can be pursued in the independent phase of this proposal. Continued training with the candidate’s advisor and expert collaborators will prepare him to succeed in his goal to run an independent research group in which he mentors investigators of all levels and pursues hypotheses aimed at understanding etiologies of neurodegenerative disease.