RNA BINDING PROTEINS IN EPILEPSY AND NEUROLOGIC DISEASE

癫痫和神经系统疾病中的 RNA 结合蛋白

• 批准号: 2903621
• 负责人: Miklos Toth
• 金额: $ 30.03万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-12-13 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2903621
• 关键词: RNA binding protein; antibody titering; autoantibody; autoimmune disorder; binding sites; central nervous system disorders; chemical kinetics; epilepsy; fragile X syndromes; gel mobility shift assay; genetically modified animals; human genetic material tag; human tissue; immunoprecipitation; laboratory mouse; neurogenetics; posttranscriptional RNA processing; protein protein interaction

DESCRIPTION (from applicant's abstract): This is a competing continuation proposal of a grant funded to study the novel Jerky protein and its role in epilepsy. The mouse line defective in the jerky gene shows epileptic seizures and our work has shown that consistent with its mutant phenotype, jerky is transcribed at a relatively high level in neurons of the central nervous system and that Jerky binds mRNA. We also showed that antibodies recognizing Jerky are present in sera of patients suffering of a certain from of autoimmune neuronal degeneration (paraneoplastic disorders, PND). Other studies suggested that the human jerky gene is a candidate for childhood absence epilepsy (CAE). We now understand Jerky to be a prototypic member of an evolutionarily conserved family of RNA binding proteins (RNPs) containing a novel RNA binding motif. RNPs are trans-acting factors mediating posttranscriptional processing of mRNAs and pre-mRNAs, including splicing, polyadenylation, transport, targeting, stability and translation. We hypothesize that lack of Jerky in mutant mice leads to a deficiency in the processing of certain mRNAs compromising neuronal functions that results in seizures. We also show that lack of FMRP (Fragile X Mental Retardation Protein), another RNP whose inactivation causes fragile X syndrome and which is believed to be involved in mRNA processing, also results in seizures in mice. This finding is consistent with the high incidence of seizures in fragile X patients. Since FMRP-deficient animals represent a second example of a situation in which abnormalities in an RNP result in seizures, we suggest that RNP dysfunction may be more general disease mechanism in epilepsy. Due to the potential importance of RNPs in epilepsy, the focus of our current grant application is to study the cellular role of Jerky, Jerky-like proteins, and FMRP. We propose I) to analyze the RNA binding properties of the human JERKY protein and a similar human protein HHJRK, II) to identify the cellular binding targets of JERKY and FMRP (by a method recently developed in our laboratory) and to assign functions for these targets, and 3) to employ Jerky autoantibodies as tool to study Jerky-RNA complexes. These proposed experiments will establish the jerky family as a distinct group of RNPs with a novel RNA binding motif. Also, specifying targets for JERKY and FMRP will allow us to link these targets to cellular pathways and ascertain how these pathways contribute to the overall function of these proteins. Finally, these experiments will aid in our understanding of certain aspects of the pathogenesis of epilepsy and autoimmune diseases.

描述（来自申请人的摘要）：这是一个竞争性的延续 一项资助研究新的牛肉干蛋白及其在 癫痫缺乏jerky基因的老鼠品系表现为癫痫发作 我们的工作表明，与其突变表型一致，肉干是 在中枢神经系统的神经元中以相对高的水平转录 而“肉干”会结合mRNA我们还发现，识别牛肉干的抗体 存在于患有某种自身免疫性神经元疾病的患者的血清中 副肿瘤性疾病（Paraneoplastic Disorders，PND）。其他研究表明， 人类jerky基因是儿童失神癫痫（CAE）候选基因。我们现在 我认为Jerky是进化保守的 RNA结合蛋白（RNP）家族，包含一个新的RNA结合基序。 RNP是介导mRNA转录后加工的反式作用因子 和前mRNA，包括剪接、多聚腺苷酸化、转运、靶向， 稳定性和翻译。我们假设突变小鼠缺乏肉干 导致某些mRNA的加工缺陷， 导致癫痫发作的功能。我们还表明，缺乏FMRP（脆性X 精神发育迟滞蛋白），另一种RNP，其失活导致脆性X 综合征，据信参与mRNA加工，也导致 在小鼠癫痫发作中的作用这一发现与高发病率相一致， 脆性X患者的癫痫发作。由于缺乏FMRP的动物代表了第二个 在RNP异常导致癫痫发作的情况下，我们 提示RNP功能障碍可能是癫痫更普遍发病机制。 由于RNP在癫痫中的潜在重要性，我们目前的重点是 基金申请是研究Jerky，Jerky样蛋白质的细胞作用， 的FMRP。我们建议I）分析人的RNA结合特性， JERKY蛋白和类似的人蛋白HHJRK，II）来鉴定细胞内的 JERKY和FMRP的结合靶点（通过我们最近开发的方法， 实验室），并为这些目标分配功能，以及3）使用Jerky 自身抗体作为研究Jerky-RNA复合物的工具。这些拟议的实验 将建立牛肉干家庭作为一个独特的RNP组与一个新的RNA 结合基序此外，指定JERKY和FMRP的目标将允许我们 将这些靶点与细胞通路联系起来， 有助于这些蛋白质的整体功能。最后这些 实验将有助于我们理解某些方面的 癫痫和自身免疫性疾病的发病机制。