Investigating disease Mechanisms in C9orf72-linked ALS/FTD

 描述(申请人提供)：核苷酸重复元件，包括微卫星或短串联重复，在真核基因组中很常见。短核苷酸重复序列的扩展与近40种不同类型的遗传疾病有关，主要是神经和神经肌肉疾病。我们对人类基因组中这些重复元件如何导致疾病的理解仍处于初级阶段。最近，C9orf72非编码区的六核苷酸重复序列的扩张与神经退行性疾病肌萎缩侧索硬化症(ALS)和额颞部痴呆(FTD)有关。ALS以运动神经元丧失为特征，C9orf72重复扩增是家族性和散发性ALS最常见的遗传原因。FTD的特点是大脑的额叶和颞叶退化，是65岁以上人群中第二常见的痴呆类型；C9orf72重复扩增也是FTD最常见的遗传原因之一。C9orf72重复扩增也被发现与阿尔茨海默病和亨廷顿病有关。为了帮助减轻与这些疾病相关的公共卫生负担，重要的是了解其发病机制。我们最近发现，C9orf72核苷酸重复结构启动了疾病的分子级联反应。该项目的目标是阐明核苷酸重复扩张(如C9orf72中的核苷酸重复扩张)导致分子缺陷和神经元毒性的机制。其具体目的是确定和表征重复扩大的关键生化特征，描绘发病机制的发生途径，并确定潜在的干预策略。这些拟议的研究结合了生化、分子和遗传学的方法，有望深入了解与核苷酸重复相关的神经退行性变的基本机制，最终可能导致治疗相关神经退行性疾病的新方法。

 DESCRIPTION (provided by applicant): Nucleotide repeat elements, including microsatellites or short tandem repeats, are common in eukaryotic genomes. Expansions of short nucleotide repeats have been linked to nearly 40 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 at its infancy. Recently, a hexanucleotide repeat expansion in a noncoding region of C9orf72 was linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is characterized by loss of motor neurons, and the C9orf72 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 for people older than 65; the C9orf72 repeat expansion is also one of the most common genetic causes for FTD. The C9orf72 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 the pathogenesis. We have recently discovered that the C9orf72 nucleotide repeat structures initiate molecular cascades of disease. The goal of the proposed project is to elucidate the mechanisms through which nucleotide repeat expansions, such as that in C9orf72, lead to molecular defects and neuronal toxicity. The specific aims are to identify and characterize key biochemical features of the repeat expansion, to delineate the pathways through which the pathogenesis is generated, and to identify potential intervention strategies. The proposed studies, which combine biochemical, molecular, and genetic approaches, are expected to provide insight into fundamental mechanisms of neurodegeneration associated with nucleotide repeats that may ultimately leads to novel approaches for treating relevant neurodegenerative diseases.