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，仍是一个尚未解决的问题。 生物医学挑战赛。基因的发现为研究 几种神经退行性疾病的分子机制。最近，一种六核苷酸 C9orf72基因非编码区的重复扩增与 神经退行性疾病肌萎缩侧索硬化症(ALS)和额颞叶痴呆 (FTD)。ALS以运动神经元丧失为特征，C9orf72突变代表 家族性和散发性肌萎缩侧索硬化症最常见的遗传原因。FTD的特点是 大脑额叶和颞叶的变性，是第二常见的 65岁以上人群的痴呆症类型；C9orf72突变也是最常见的 FTD的遗传原因。C9orf72突变也被发现与阿尔茨海默病有关 和亨廷顿氏症。尽管付出了巨大的努力和快速的进展，但我们对 C9orf72连锁ALS/FTD的发病机制和治疗策略仍处于早期阶段 各阶段。为了帮助减轻与这些疾病相关的公共卫生负担，重要的是 以了解其发病机制。我们最近发现， C9ORF72在调节自噬及相关代谢过程中发挥重要作用。 提示对C9orf72功能的进一步研究可能有助于阐明 ALS/FTD的发病机制。拟议项目的目标是阐明这些机制。 通过C9orf72功能失调导致分子缺陷和神经元 毒性。具体目的是确定C9orf72通过哪些中央机制 调节自噬和相关新陈代谢，以描绘通过 发病机制是产生的，并确定潜在的干预策略。建议数 结合了生化、分子和遗传学方法的研究有望 提供对ALS/FTD神经变性的基本机制的洞察，可能 最终导致治疗这些毁灭性的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.