Elucidating the neural specific functions of the RNA-binding protein Caper in neural development and neurodegeneration

阐明 RNA 结合蛋白 Caper 在神经发育和神经变性中的神经特异性功能

• 批准号: 10577059
• 负责人: Eugenia C Olesnicky
• 金额: $ 43.8万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577059
• 关键词: Adult; Afferent Neurons; Age; Aging; Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Axon; Behavior; Behavioral Assay; Biochemical Genetics; Biochemistry; Biological Assay; Brain; Capers; Cell Death; Cell Polarity; Cells; Collection; Complex; Data; Defect; Dendrites; Development; Drosophila genus; Drosophila melanogaster; Fragile X Syndrome; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Goals; Human; Immunofluorescence Immunologic; Immunoprecipitation; Knowledge; Light; Longevity; Modeling; Molecular; Molecular Genetics; Morphogenesis; Morphology; Motor Neurons; Mutation; Nature; Nerve Degeneration; Nervous System Trauma; Nervous system structure; Neurites; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuromuscular Junction; Neurons; Neurophysiology - biologic function; Orthologous Gene; Outcome; Pathology; Phenotype; Plant Roots; Play; Post-Transcriptional Regulation; Process; Proteins; Public Health; RNA; RNA Splicing; RNA-Binding Proteins; Reagent; Regulation; Regulator Genes; Research; Ribonucleoproteins; Role; Spinal Muscular Atrophy; Testing; Time; Tissues; Translations; Up-Regulation; Work; aging brain; cell type; combinatorial; genetic approach; genetic manipulation; healthy aging; insight; locomotor deficit; mutant; nervous system disorder; neurodegenerative phenotype; neurodevelopment; neurogenesis; neuron apoptosis; protein function; relating to nervous system

Project Summary/Abstract Post-transcriptional gene regulation is a fundamental mechanism that helps regulate the development and healthy aging of the nervous system. Mutations that disrupt the function of RNA-binding proteins (RBPs), which regulate post-transcriptional gene regulation, have increasingly been implicated in neurological disorders including amyotrophic lateral sclerosis, Fragile X Syndrome, and spinal muscular atrophy. Interestingly, although the majority of RBPs are expressed widely within diverse tissue types, the nervous system is often particularly sensitive to their dysfunction. The long-term goal of this project is to begin to elucidate how aberrant RNA regulation that results from the dysfunction of ubiquitously expressed RBPs, leads to tissue specific pathologies that underlie neurological diseases. To this end, the highly conserved splicing factor Caper will be used as a model. Caper is widely expressed throughout development and is required for the development of Drosophila sensory and motor neurons. Furthermore, caper dysfunction causes neurodegeneration and results in adult locomotor deficits. Though little is known about the function of the human caper ortholog, RBM39, it is expressed within the nervous system suggesting its neural functions may be conserved. The research proposed within this application will test the hypothesis that Caper regulates RNA targets in a combinatorial manner within neuronal cells by participating in specific ribonucleoprotein complexes (RNPs) within the nervous system. We have identified proteins encoding RBPs that interact with Caper only within the brain, along with neural specific Caper target RNAs. Using the highly tractable model, Drosophila, tissue specific molecular genetic manipulations will be used in conjunction with biochemistry to determine the extent to which Caper functions combinatorially with these RBPs to direct neurogenesis and protect the aging brain from neurodegeneration. Furthermore, we will further characterize the neurodegenerative phenotypes associated with caper dysfunction to determine which cell types are undergoing cell death in the aging brain. Since aberrant RNA regulation has emerged as a common theme in various neurodegenerative and neurodevelopmental disorders, the knowledge gained from this study has broad implications for understanding and treating neurological disorders.

项目总结/摘要 转录后基因调控是一种基本的机制，有助于调节发育， 神经系统的健康老化。破坏RNA结合蛋白（RBP）功能的突变， 调节转录后基因调控，越来越多地涉及神经系统疾病 包括肌萎缩侧索硬化症、脆性X综合征和脊髓性肌萎缩。有趣的是， 尽管大多数RBP在不同的组织类型中广泛表达，但神经系统通常 对他们的功能障碍特别敏感。这个项目的长期目标是开始阐明如何 由普遍表达的RBP功能障碍引起的RNA调节异常，导致组织 神经系统疾病背后的特殊病理为此，高度保守的剪接因子Caper 将被用作模型。Caper在整个开发过程中广泛表达， 果蝇感觉和运动神经元的发育。此外，跳跃功能障碍会导致 神经变性并导致成年运动缺陷。虽然我们对它的功能知之甚少， 人刺山柑同源基因RBM 39，它在神经系统内表达，表明其神经功能可能 要保守。本申请中提出的研究将测试Caper调节RNA的假设 通过参与特异性核糖核蛋白复合物， （RNP）在神经系统中。我们已经确定了编码RBP的蛋白质，它们只与Caper相互作用。 在脑内，沿着神经特异性Caper靶RNA。使用高度易处理的模型，果蝇， 组织特异性分子遗传操作将与生物化学结合使用， Caper与这些RBP组合发挥作用以指导神经发生和保护衰老的程度 大脑神经退化此外，我们将进一步表征神经退行性表型 以确定哪些细胞类型正在老化的大脑中经历细胞死亡。 由于异常的RNA调节已经成为各种神经退行性疾病和 神经发育障碍，从这项研究中获得的知识具有广泛的意义， 和治疗神经系统疾病

项目成果

The conserved alternative splicing factor caper regulates neuromuscular phenotypes during development and aging.

• DOI: 10.1016/j.ydbio.2021.01.011
• 发表时间: 2021-05
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Titus MB;Wright EG;Bono JM;Poliakon AK;Goldstein BR;Super MK;Young LA;Manaj M;Litchford M;Reist NE;Killian DJ;Olesnicky EC
• 通讯作者: Olesnicky EC

The identification of protein and RNA interactors of the splicing factor Caper in the adult Drosophila nervous system.

• DOI: 10.3389/fnmol.2023.1114857
• 发表时间: 2023
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Titus, M. Brandon;Chang, Adeline W.;Popitsch, Niko;Ebmeier, Christopher C.;Bono, Jeremy M.;Olesnicky, Eugenia C.
• 通讯作者: Olesnicky, Eugenia C.