Tau missplicing caused by RNA processing proteins located on chromosome 21

由位于 21 号染色体上的 RNA 加工蛋白引起的 Tau 错误剪接

• 批准号: 7295542
• 负责人: ATHENA ANDREADIS
• 金额: $ 18.09万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-20 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7295542
• 关键词: Affinity; Alternative Splicing; Alzheimer' s Disease; Biological Markers; Brain; Candidate Disease Gene; Cell Nucleus; Cells; Characteristics; Chromosomes, Human, Pair 21; Co-Immunoprecipitations; Collaborations; Complex; Confocal Microscopy; Congenital chromosomal disease; Defect; Dementia; Diagnosis; Diagnostic; Down Syndrome; Event; Exons; Freezing; Frontotemporal Dementia; Gel; Genes; Goals; Grant; Hereditary Disease; Heterogeneous Nuclear RNA; Human; Immunohistochemistry; Immunoprecipitation; In Situ; In Vitro; Incidence; Individual; Laboratories; Laboratory Study; Legal patent; Length; Ligands; Localized; Mental Retardation; Methods; Molecular Profiling; Myotonic Dystrophy; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Nuclear; Overdose; Parkinsonian Disorders; Pathology; Phosphorylation; Phosphotransferases; Prevalence; Protein Isoforms; Protein Overexpression; Proteins; Publications; RNA; RNA Processing; RNA Splicing; Regulation; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Small Interfering RNA; Structure; Study Subject; Substrate Specificity; Symptoms; Syndrome; System; Test Result; Testing; Therapeutic; Transfection; Work; abnormally phosphorylated tau; brain tissue; crosslink; early onset; human disease; mRNA Precursor; mutant; novel; tau Proteins; tau phosphorylation; tau-1; therapeutic target

DESCRIPTION (provided by applicant): Tau missplicing caused by RNA processing proteins located on chromosome 21 Trisomy 21 (Down syndrome, DS), the most common chromosomal disorder (incidence of about 1:800), results in morphological defects, mental retardation and early-onset dementia with Alzheimer characteristics, including neurofibrillary tangles. Neurofibrillary tangles are causative and diagnostic structures found in the brains of all dementia sufferers, including DS, Alzheimer's disease, frontotemporal dementia with Parkinsonism (FTDP) and myotonic dystrophy 1. The major component of tangles is abnormally phosphorylated tau protein. The neuronal microtubule-associated protein tau undergoes complex alternative splicing and differential phosphorylation, producing isoforms with different ligand affinities and functions. Our work and that of others has shown that misregulation of tau exon 10 splicing causes FTDP and that exon 10 ratios are also altered in AD. In this exploratory grant, we propose to test the hypothesis that an overdose of RNA processing proteins located on chromosome 21 causes errors in the splicing regulation of tau and its splicing regulator clk2, which in turn contributes to the early dementia aspects of DS. The aims of the grant are to investigate: 1) Regulation of tau and clk2 splicing by RNA processing proteins located on chromosome 21. These include SR-A4, RBM11, U2AF35 and PCBP3 (hnRNPE3). Our work has shown that hnRNPE2, a close relative of hnRNPE3, regulates tau splicing. 2) Possible missplicing of tau and clk2 by incorrect expression of phosphorylation factors located on chromosome 21. These include MAKV (HUNK), KID2 (SFN1LK) and MNB (Dyrk1A). Dyrk1A localizes to nuclear speckles and our work has shown that it also phosphorylates factors which regulate splicing of tau exon 10. 3) The expression and localization profile of factors located on chromosome 21 that we find to influence tau and clk2 in brains of human individuals who are normal or diagnosed with DS and AD. Results from testing this novel hypothesis should 1) establish novel predictive biomarkers for trisomy 21 dementia, 2) uncover additional connections between trisomy 21 mental retardation and early-onset dementia and 3) offer the possibility of treatment options via manipulation of kinases with a restricted expression profile and substrate specificity. The prevalence of the syndrome and its clear connection to AD make this hypothesis a very relevant and potentially fruitful subject of study. Tau missplicing caused by RNA processing proteins located on chromosome 21 These studies will clarify the elusive connections between tau and the early-onset dementia aspect of Down syndrome. They may also help us find therapeutic targets and treatment options for this extremely prevalent and agonizing genetic disease.

描述（由申请人提供）：由位于21号染色体21三体（唐氏综合征，DS）上的RNA加工蛋白引起的Tau错误剪接，是最常见的染色体疾病（发病率约为1：800），导致形态缺陷、精神发育迟滞和具有阿尔茨海默特征的早发性痴呆，包括神经系统缠结。神经元缠结是在所有痴呆症患者的大脑中发现的病因和诊断结构，包括DS、阿尔茨海默病、额颞叶痴呆伴帕金森综合征（FTDP）和强直性肌营养不良1。缠结的主要成分是异常磷酸化的tau蛋白。神经元微管相关蛋白tau经历复杂的选择性剪接和差异磷酸化，产生具有不同配体亲和力和功能的同种型。我们和其他人的工作表明，tau外显子10剪接的错误调节导致FTDP，AD中外显子10的比例也发生了改变。在这项探索性资助中，我们建议测试一个假设，即位于21号染色体上的过量RNA加工蛋白会导致tau及其剪接调节因子clk 2的剪接调节错误，这反过来又会导致DS的早期痴呆。该基金的目的是研究：1）位于21号染色体上的RNA加工蛋白对tau和clk 2剪接的调节。这些包括SR-A4、RBM 11、U2 AF 35和PCBP 3（hnRNPE 3）。我们的工作表明，hnRNPE 2，hnRNPE 3的近亲，调节tau剪接。2)位于21号染色体上的磷酸化因子的不正确表达可能导致tau和clk 2的错误剪接。这些包括MAKV（HUNK），KID 2（SFN 1 LK）和MNB（Dyrk 1A）。Dyrk 1A定位于核斑点，我们的工作表明它也磷酸化调节tau外显子10剪接的因子。3)我们发现位于21号染色体上的因子的表达和定位概况影响正常或诊断为DS和AD的人类个体的大脑中的tau和clk 2。测试这一新假设的结果应该：1）建立21三体痴呆的新预测生物标志物，2）揭示21三体精神发育迟滞和早发性痴呆之间的其他联系，3）通过操纵具有受限表达谱和底物特异性的激酶提供治疗选择的可能性。该综合征的患病率及其与AD的明确联系使这一假设成为一个非常相关且可能富有成果的研究课题。位于21号染色体上的RNA加工蛋白引起的Tau错误剪接这些研究将阐明tau与唐氏综合征早发性痴呆之间难以捉摸的联系。它们还可以帮助我们找到这种极其普遍和痛苦的遗传疾病的治疗靶点和治疗方案。