Investigating the role of C9orf72 in autophagic and metabolic dysregulation in ALS/FTD

神经退行性变是一个日益严重的公共卫生问题， 生物医学挑战遗传学的发现为研究人类基因组提供了新的途径。 几种神经退行性疾病的分子机制最近，一种六核苷酸 在C9 orf 72基因的非编码区的重复扩增被链接到 神经退行性疾病肌萎缩侧索硬化症（ALS）和额颞叶痴呆 （FTD）。ALS的特征在于运动神经元的丧失，并且C9 orf 72突变代表了ALS的特征。 是家族性和散发性肌萎缩侧索硬化症最常见的遗传原因。FTD的特征在于 大脑额叶和颞叶的退化，是第二常见的 一种65岁以上的痴呆症; C9 orf 72突变也是最常见的 FTD的遗传原因。C9 orf 72突变也被发现有助于阿尔茨海默病 和亨廷顿舞蹈症。尽管作出了巨大努力并取得了迅速进展，但我们对 C9 orf 72连锁ALS/FTD的疾病机制和治疗策略仍处于早期阶段， 阶段为了帮助减轻与这些疾病相关的公共卫生负担， 以了解发病机制。我们最近发现， C9 orf 72在自噬和相关代谢过程的调节中起重要作用， 这表明对C9 orf 72功能的进一步研究可以阐明 ALS/FTD发病机制。该项目的目标是阐明 C9 orf 72功能失调导致分子缺陷， 毒性具体的目的是确定C9 orf 72 调节自噬和相关的代谢，以描绘通过哪些途径， 产生发病机制，并确定潜在的干预策略。拟议 结合了生物化学、分子生物学和遗传学方法的联合收割机研究， 深入了解ALS/FTD中神经变性的基本机制， 最终导致治疗这些破坏性神经退行性疾病的新方法。

Neurodegeneration is an increasing public health issue and remains an unsolved biomedical challenge. Genetic discoveries have provided news avenues for investigating the molecular mechanisms of several neurodegenerative diseases. Recently, a hexanucleotide repeat expansion in a noncoding region of the C9orf72 gene 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 mutation 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 mutation is also the most common genetic causes for FTD. The C9orf72 mutation is also found to contribute to Alzheimer’s disease and Huntington’s disease. Despite intense efforts and rapid advances, our understanding of the disease mechanisms and treatment strategies for C9orf72-linked ALS/FTD are still at the early stages. 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 C9orf72 plays an important role in the regulation of autophagy and related metabolic processes, suggesting that further studies of C9orf72 functions could shed light on the mechanism of ALS/FTD pathogenesis. The goal of the proposed project is to elucidate the mechanisms through which dysregulation of C9orf72 functions leads to molecular defects and neuronal toxicity. The specific aims are to identify the central mechanisms through which C9orf72 regulates autophagy and related metabolism, 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 in ALS/FTD that may ultimately leads to novel approaches for treating these devastating neurodegenerative diseases.