Molecular Basis of Pathogenic Cascades in ALS/FTD Initiated from C9orf72 Hexanucleotide Repeat Expansion

项目摘要 核苷酸重复元件，包括微卫星或短串联重复序列，是 在真核基因组中很常见。短核苷酸重复序列的扩展与 超过50种不同类型的遗传性疾病，主要是神经和神经肌肉疾病。 我们对人类基因组中的这些重复元件如何导致疾病的理解仍然 在它的初级阶段。C9orf72基因非编码区的六核苷酸重复序列扩增 与神经退行性疾病肌萎缩侧索硬化症(ALS)和 额颞性痴呆(FTD)。ALS的特点是运动神经元丢失，C9orf72 六核苷酸重复序列扩增是两个家族性遗传病最常见的遗传原因 和散发性肌萎缩侧索硬化症。FTD的特征是额叶和颞叶的变性 C9orf72是65岁以上人群中第二常见的痴呆症类型 六核苷酸重复扩增也是FTD最常见的遗传原因。这种重复 研究还发现，扩张也会导致阿尔茨海默病和亨廷顿病。帮助 为了减轻与这些疾病相关的公共卫生负担，重要的是了解 它们的致病机制。存在多种假说来解释致病原因 C9orf72连锁ALS/FTD的潜在机制。拟议项目的目标是 阐明C9orf72六核苷酸重复序列扩增的新机制 对分子缺陷和神经元毒性，重点是功能获得机制。这个 具体目的是确定由C9orf72引发的以前未知的致病级联 六核苷酸重复扩增。这些新的致病级联包括但不限于 C9orf72的TO、RNA毒性和非规范翻译产物 六核苷酸重复扩增。我们提出了一系列基础研究，这些研究结合了 生物化学、分子和遗传学方法，以阐明导致 ALS/FTD的发病机制和确定潜在的干预策略。成功完成 预计该项目的实施将提供对 ALS/FTD的神经变性最终可能导致新的治疗方法 ALS/FTD及其他相关神经退行性疾病。

Project Summary Nucleotide repeat elements, including microsatellites or short tandem repeats, are common in eukaryotic genomes. Expansions of short nucleotide repeats have been linked to over 50 different types of genetic disorders, primarily neurological and neuromuscular disorders. Our understanding of how these repeat elements in the human genome cause diseases is still in its infancy. A hexanucleotide repeat expansion in a noncoding region of the C9orf72 gene has been linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is characterized by loss of motor neurons, and the C9orf72 hexanucleotide repeat expansion represents the most common genetic cause of both familial and sporadic ALS. FTD is characterized by degeneration of the frontal and temporal lobes of the brain and is the second-most common type of dementia in people older than 65; the C9orf72 hexanucleotide repeat expansion is also the most common genetic cause of FTD. This repeat expansion is also found to contribute to Alzheimer’s disease and Huntington’s disease. To help relieve the public health burden associated with these diseases, it is important to understand the mechanisms underlying their pathogenesis. Multiple hypotheses exist to explain the pathogenic mechanisms underlying C9orf72-linked ALS/FTD. The goal of the proposed project is to elucidate novel mechanisms through which the C9orf72 hexanucleotide repeat expansion leads to molecular defects and neuronal toxicity, focusing on gain-of-function mechanisms. The specific aims are to identify previously unknown pathogenic cascades initiated by the C9orf72 hexanucleotide repeat expansion. These novel pathogenic cascades include, but are not limited to, RNA toxicity and non-canonical translation products resulting from the C9orf72 hexanucleotide repeat expansion. We propose a series of fundamental studies that combine biochemical, molecular, and genetic approaches to shed light on the novel pathways leading to ALS/FTD pathogenesis and to identify potential intervention strategies. Successful completion of the project is expected to provide insights into fundamental mechanisms of neurodegeneration in ALS/FTD that may ultimately lead to novel approaches for treating ALS/FTD and other relevant neurodegenerative diseases.