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Cellular and Molecular Mechanisms of FUS-related ALS/FTD

FUS相关ALS/FTD的细胞和分子机制

基本信息

批准号：
9763021
负责人：
Udai B Pandey
金额：
$ 38.41万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763021
关键词：
Amyotrophic Lateral Sclerosis Animal Model Animals Award Axon Behavioral Assay Biochemical Biogenesis Biological Assay Brain CAG repeat Cell Culture Techniques Cell model Cell physiology Complex Cytoplasm Cytoplasmic Granules Defect Disease Drosophila genus Ectopic Expression Frontotemporal Dementia Functional disorder Genes Genetic Genetic Screening Genetic Transcription Goals Homologous Gene Human Light Link Longevity Lower Organism Mammalian Cell Mediating Metabolism MicroRNAs Modeling Molecular Motor Neurons Mutate Mutation Myotonic Dystrophy Nerve Degeneration Neurodegenerative Disorders Neuromuscular Junction Neurons Nuclear Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Physiological Proteins RNA RNA Interference RNA Splicing RNA-Binding Protein FUS RNA-Binding Proteins Small Nuclear RNA Spinal Muscular Atrophy Structure Therapeutic Intervention Toxic effect Translations Ubiquitin Vertebrates Work cellular pathology cofactor disease-causing mutation fly frontotemporal degeneration frontotemporal lobar dementia-amyotrophic lateral sclerosis human disease in vivo induced pluripotent stem cell knock-down molecular pathology motor neuron degeneration mutant novel patient subsets protein TDP-43 recruit stress granule trafficking transcriptome transcriptome sequencing transcriptomics

项目摘要

ALS is a late-onset progressive neurodegenerative disease caused by degeneration of motor neurons, and a disease hallmark is the accumulation of ubiquitin-positive aggregates in neuronal cytoplasm. FUS was identified as genes mutated in both familial and sporadic forms of ALS. In fact, a subset of patients with frontotemporal dementia (FTD) show FUS pathology. FUS, similar to TDP-43, is an RNA binding protein implicated in multiple aspects of RNA metabolism, including splicing, trafficking, and translation. The precise mechanisms of mutated FUS in ALS pathogenesis are not known. To understand the molecular mechanisms of FUS-mediated neurodegeneration, we developed cellular (mammalian primary neuronal and patient-derived iPSC motor neuron) and Drosophila models that recapitulate key features of human disease including cytoplasmic mislocalization, neuromuscular junction defects, locomotor dysfunctions, reduced life span, perturbed stress granule dynamics and toxicity. We discovered muscleblind and drosha as unexpected and novel modifiers of mutant FUS toxicity. MBNL proteins, highly conserved from lower organisms to vertebrates, have been implicated in many neurodegenerative disorders, such as myotonic dystrophy and CAG repeat diseases. The long-term goal is to identify modifiers of FUS toxicity and understand their molecular mechanisms using mammalian cell culture and Drosophila models. The objective of our current application is to determine how muscleblind and drosha modulate FUS-mediated toxicity in Drosophila and FUS iPSC motor neurons. We hypothesize that muscleblind and drosha regulate RNA splicing, SG dynamics and miRNA biogenesis that is perturbed by pathogenic mutations in FUS. We will examine the impact of muscleblind and drosha on cellular and molecular pathologies in FUS-associated neurodegeneration. We expect to dissect the molecular pathways that could be exploited for developing therapeutic interventions for ALS/FTD patients.

肌萎缩侧索硬化症是一种迟发性进行性神经退行性疾病，由运动退行性改变引起。神经元，疾病的标志是泛素阳性聚集在神经元胞质。FUS被鉴定为在家族性和散发形式的FUS中的基因突变肌萎缩侧索硬化。事实上，部分额颞性痴呆(FTD)患者表现出FUS病理。 FUS类似于TDP-43，是一种RNA结合蛋白，与RNA的多个方面有关新陈代谢，包括剪接、运输和翻译。突变的精确机制 FUS在ALS发病机制中的作用尚不清楚。为了了解FUS介导的神经退行性变的分子机制，我们开发了细胞(哺乳动物初级神经元和病人来源的IPSC运动神经元)和果蝇这些模型概括了人类疾病的关键特征，包括细胞质定位错误，神经肌肉接头缺陷，运动功能障碍，寿命缩短，不安的压力颗粒动力学和毒性。我们发现肌盲和DROSHA是意想不到的和新颖的突变型FUS毒性修饰剂。MBNL蛋白，在低等生物中高度保守脊椎动物与许多神经退行性疾病有关，如肌强直营养不良和CAG重复疾病。长期目标是确定FUS毒性的修饰物。并利用哺乳动物细胞培养和果蝇了解它们的分子机制模特们。我们目前应用的目标是确定肌肉盲和DROSHA如何调节果蝇和FUS iPSC运动神经元中FUS介导的毒性。我们假设肌盲和DROSHA调控RNA剪接、SG动力学和miRNA生物发生，即对FUS的致病突变感到不安。我们将研究肌肉盲人和 DROSHA关于FUS相关神经退行性变的细胞和分子病理学。我们预计剖析可用于开发治疗药物的分子途径对ALS/FTD患者的干预。