Tau missplicing caused by RNA processing proteins located on chromosome 21

描述（由申请人提供）：由位于21号染色体上的RNA加工蛋白引起的Tau错误剪接21三体（唐氏综合症，DS）是最常见的染色体疾病（发病率约为1:800），导致形态缺陷，智力迟钝和具有阿尔茨海默病特征的早发性痴呆，包括神经原纤维缠结。神经原纤维缠结是在所有痴呆患者的大脑中发现的病因和诊断结构，包括退行性痴呆、阿尔茨海默病、帕金森额颞叶痴呆（FTDP）和肌强直性营养不良。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异构体。我们和其他人的研究表明，tau外显子10剪接的错误调节导致FTDP，并且外显子10比率也在AD中发生改变。在这项探索性研究中，我们提出验证21号染色体上过量的RNA加工蛋白会导致tau及其剪接调节因子clk2的剪接调节错误，从而导致DS的早期痴呆方面的假设。该基金的目的是研究：1)21号染色体上的RNA加工蛋白对tau和clk2剪接的调控。这些包括SR-A4， RBM11， U2AF35和PCBP3 （hnRNPE3）。我们的工作表明hnRNPE2， hnRNPE3的近亲，调节tau剪接。2) 21号染色体磷酸化因子的错误表达可能导致tau和clk2的错误剪接。这些包括MAKV (HUNK), KID2 （SFN1LK）和MNB （Dyrk1A）。Dyrk1A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) 21号染色体上影响tau和clk2在正常或诊断为DS和AD的人大脑中的表达和定位谱。验证这一新假设的结果应该1)建立21三体痴呆的新的预测性生物标志物，2)揭示21三体智力迟钝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。该综合征的流行及其与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。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。它们也可能帮助我们找到治疗靶点和治疗方案，以治疗这种极其普遍和痛苦的遗传疾病。

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.