Mechanism of FUS Mutations in the Pathogenesis of ALS

FUS突变在ALS发病机制中的作用

• 批准号: 8331710
• 负责人: Eric J Huang
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331710
• 关键词: Address; Adult; Affect; Affinity; Aging; Amyotrophic Lateral Sclerosis; Animal Model; Award; Behavioral; Binding; Biological Models; Biomedical Research; C-terminal; Cancer Biology; Cell Death; Cell model; Chromosomes, Human, Pair 16; Communities; Cytoplasm; DNA; Data; Defect; Development; Diabetes Mellitus; Discipline; Disease; Endoplasmic Reticulum; Familial Amyotrophic Lateral Sclerosis; Funding; Funding Mechanisms; Genes; Genetic; Goals; Health; Human; Human Chromosomes; Investigation; Lead; Maintenance; Malignant - descriptor; Malignant Neoplasms; Maps; Mental Health; Mission; Mitochondria; Modeling; Motor; Motor Neurons; Muscle; Mutate; Mutation; Myeloid Leukemia; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Oncogenes; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Pilot Projects; Polyribosomes; Preclinical Drug Evaluation; Protein Biosynthesis; Proteins; RNA; RNA Transport; RNA chemical synthesis; RNA-Binding Protein FUS; RNA-Binding Proteins; Research; Respiratory Failure; Ribosomal Proteins; Spinal; Stress; Synapses; Therapeutic; Transgenic Mice; Transgenic Organisms; United States Department of Veterans Affairs; base; carcinogenesis; endoplasmic reticulum stress; high reward; insight; liposarcoma; motor neuron degeneration; mouse model; mutant; nerve supply; neuron loss; neuronal survival; neuropathology; new therapeutic target; novel; protein aggregate; research study; response; sarcoma; synaptogenesis; therapeutic target; wasting

DESCRIPTION (provided by applicant): ALS is a fatal disease caused by the selective degeneration of motor neurons in the central nervous system. Patients with ALS suffer from severe muscle wasting/weakness and eventually die from respiratory failure. Recent genetic data have shown that mutations in the FUS gene can be identified in more than 5% of patients with familial and sporadic ALS. The identification of additional genetic causes, such as FUS mutations, strongly indicate the urgent needs to develop new model systems to understand these mutations and to identify therapeutic targets for these devastating diseases. One important pathological feature in ALS patients with FUS mutations is the presence of abnormal protein aggregates in motor neurons prior to their degeneration. However, it is unclear if abnormal protein aggregates directly contribute to the degeneration of the motor neurons. Based on the function of FUS as a RNA binding protein, we hypothesize that mutation in FUS interferes with normal RNA/protein synthesis, which ultimately leads to cell death and the degeneration of motor neuron synapses. To further investigate the mechanisms of FUS mutations, we propose to establish cellular and mouse models to characterize the effects of FUS mutant proteins in RNA transport and synthesis. Our goal is to establish both cellular and transgenic mouse models to determine how mutant FUS proteins lead to neuronal cell death and the maintenance of the neuromuscular junction. In support of this view, our data indicate that spinal motor neurons in transgenic mice expressing mutant FUS proteins show severe disruption in RNA and protein synthesis machinery. These exciting results give us the confidence that our proposed experiments are highly achievable within the two years funding period of the Therapeutic Idea Award. They further provide strong supports that these models will serve as novel platforms for the development of high throughput drug screening to identify therapeutic targets that can block cell death in motor neurons and restore innervation at the neuromuscular junction.

描述（由申请人提供）： ALS 是一种由中枢神经系统运动神经元选择性变性引起的致命疾病。 ALS 患者患有严重的肌肉萎缩/无力，最终死于呼吸衰竭。最近的基因数据显示，超过 5% 的家族性和散发性 ALS 患者可发现 FUS 基因突变。其他遗传原因（例如 FUS 突变）的鉴定强烈表明迫切需要开发新的模型系统来了解这些突变并确定这些破坏性疾病的治疗靶点。具有 FUS 突变的 ALS 患者的一项重要病理特征是运动神经元在退化之前存在异常蛋白质聚集体。然而，尚不清楚异常蛋白质聚集是否直接导致运动神经元的退化。基于FUS作为RNA结合蛋白的功能，我们假设FUS的突变会干扰正常的RNA/蛋白质合成，最终导致细胞死亡和运动神经元突触的退化。为了进一步研究FUS突变的机制，我们建议建立细胞和小鼠模型来表征FUS突变蛋白在RNA转运和合成中的影响。我们的目标是建立细胞和转基因小鼠模型，以确定突变 FUS 蛋白如何导致神经元细胞死亡和神经肌肉接头的维持。为了支持这一观点，我们的数据表明，表达突变 FUS 蛋白的转基因小鼠的脊髓运动神经元显示出 RNA 和蛋白质合成机制的严重破坏。这些令人兴奋的结果让我们相信，我们提出的实验在治疗理念奖的两年资助期内是可以实现的。他们进一步提供了强有力的支持，即这些模型将作为开发高通量药物筛选的新平台，以确定可以阻止运动神经元细胞死亡并恢复神经肌肉接头神经支配的治疗靶点。