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

研究 C9orf72 在 ALS/FTD 自噬和代谢失调中的作用

• 批准号: 9904831
• 负责人: Jiou Wang
• 金额: $ 56.75万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904831
• 关键词: Address; Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Autophagocytosis; Biochemical; Biological Models; Brain; C9ORF72; Caenorhabditis elegans; Cells; Clinical; Defect; Dementia; Disease; Equilibrium; Etiology; FRAP1 gene; Feedback; Frontotemporal Dementia; Genes; Genetic; Genetic study; Goals; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Huntington Disease; Intervention; Investigation; Knowledge; Lead; Light; Link; Lysosomes; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Molecular; Molecular Genetics; Motor Neurons; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Nucleotides; Organelles; Pathogenesis; Pathology; Pathway interactions; Patients; Physiological; Play; Predisposition; Proteins; Public Health; Quality Control; Regulation; Research; Role; Signal Transduction; Societies; Spinal Cord; System; Temporal Lobe; Tissues; Toxic effect; Untranslated RNA; Work; base; cell growth regulation; coactivator-associated arginine methyltransferase 1; effective therapy; epigenetic regulation; frontal lobe; frontotemporal lobar dementia-amyotrophic lateral sclerosis; genetic approach; insight; lipid metabolism; loss of function; neurotoxicity; news; novel; novel strategies; novel therapeutic intervention; tool; treatment strategy

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.

神经变性是一个越来越多的公共卫生问题，仍然是未解决的 生物医学挑战。遗传发现提供了调查的新闻途径 几种神经退行性疾病的分子机制。最近，是六核苷酸 在C9orf72基因的非编码区域中重复扩展与 神经退行性疾病肌营养性侧索硬化症（ALS）和额颞痴呆 （FTD）。 ALS的特征是运动神经元的丧失，C9ORF72突变代表 家庭和零星ALS的最常见遗传原因。 FTD的特征是 额叶和临时爱的变性，是第二常见的 年龄超过65岁的人的痴呆类型； C9orf72突变也是最常见的 FTD的遗传原因。还发现C9orf72突变有助于阿尔茨海默氏病 和亨廷顿氏病。尽管付出了巨大的努力和快速的进步，但我们对 C9ORF72连接ALS/FTD的疾病机制和治疗策略仍在早期 阶段。为了减轻与这些疾病相关的公共卫生烧伤，这很重要 了解发病机理的基础机制。我们最近发现 C9ORF72在调节自噬和相关代谢过程中起重要作用， 提出对C9ORF72功能的进一步研究可以阐明 ALS/FTD发病机理。拟议项目的目的是阐明机制 C9ORF72功能的失调导致分子缺陷和神经元 毒性。具体目的是确定C9orf72的中心机制 调节自噬和相关代谢，以描绘出该途径 生成发病机理，并确定潜在的干预策略。提议 结合生化，分子和遗传学方法的研究预计将是 提供有关ALS/FTD中神经变性基本机制的见解 最终导致了治疗这些毁灭性神经退行性疾病的新方法。