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: 6539824
• 负责人: Miklos Toth
• 金额: $ 30.68万
• 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/6539824
• 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（来自申请人摘要）：这是一个竞争性的延续

项目成果

Sensitivity to jerky gene dosage underlies epileptic seizures in mice.

对生涩基因剂量的敏感性是小鼠癫痫发作的基础。

• DOI: 10.1523/jneurosci.17-12-04562.1997
• 发表时间: 1997
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Donovan,GP;Harden,C;Gal,J;Ho,L;Sibille,E;Trifiletti,R;Gudas,LJ;Toth,M
• 通讯作者: Toth,M

5-HT1A receptor knockout mouse as a genetic model of anxiety.

• DOI: 10.1016/s0014-2999(03)01280-9
• 发表时间: 2003-02
• 期刊: European journal of pharmacology
• 影响因子: 5
• 作者: M. Toth

Fmrp is required for the establishment of the startle response during the critical period of auditory development.

在听觉发育的关键时期建立惊吓反应需要 Fmrp。

• DOI: 10.1016/j.brainres.2006.06.086
• 发表时间: 2006
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Yun,Seong-Wook;Platholi,Jimcy;Flaherty,MariaSol;Fu,Weimin;Kottmann,AndreasH;Toth,Miklos
• 通讯作者: Toth,Miklos

Transgenic approaches to epilepsy.

癫痫的转基因方法。

• 发表时间: 1999
• 期刊: Advances in neurology.
• 作者: Toth,M;Tecott,L
• 通讯作者: Tecott,L