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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由运动退行性变性引起的迟发性进行性神经退行性疾病