Tau missplicing caused by RNA processing proteins located on chromosome 21

描述(申请人提供)：位于21号染色体21三体(DS)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、智力低下和具有阿尔茨海默氏症特征的早发性痴呆，包括神经原纤维缠结。神经原纤维缠结是在所有痴呆症患者的大脑中发现的致病和诊断结构，包括DS、阿尔茨海默病、额颞叶痴呆伴帕金森病(FTDP)和强直性肌营养不良症1。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亚型。我们和其他人的工作表明，tau外显子10剪接的错误调节会导致FTDP，并且外显子10的比例在AD中也会改变。在这项探索性授权中，我们建议检验一种假设，即位于21号染色体上的过量RNA加工蛋白导致tau及其剪接调节因子clk2的剪接调控错误，这反过来又有助于DS的早期痴呆方面。这项资助的目的是研究：1)位于21号染色体上的RNA加工蛋白对tau和clk2剪接的调节。这些病毒包括SR-A4、RBM11、U2AF35和PCBP3(HnRNPE3)。我们的工作表明，hnRNPE2是hnRNPE3的近亲，调控tau剪接。2)位于21号染色体上的磷酸化因子的错误表达可能导致tau和clk2的错接。这些病毒包括MAKV(BUNK)、KID2(SFN1LK)和MNB(Dyrk1A)。Dyrk1A定位于核斑点，我们的工作表明它还使调节tau外显子10剪接的因子磷酸化。3)我们发现位于21号染色体上的影响tau和clk2的因子在正常或诊断为DS和AD的人的大脑中的表达和定位情况。检验这一新假说的结果应该是：1)为21三体痴呆建立新的预测生物标志物；2)发现21三体精神发育迟滞和早发性痴呆之间的其他联系；3)通过操纵表达谱和底物特异性受限的激酶，提供治疗选择的可能性。该综合征的流行及其与阿尔茨海默病的明显联系使这一假说成为一个非常相关且具有潜在成果的研究主题。位于21号染色体上的RNA加工蛋白引起的tau错接这些研究将阐明tau与唐氏综合征早发性痴呆之间难以捉摸的联系。它们还可能帮助我们为这种极其普遍和令人痛苦的遗传病找到治疗目标和治疗选择。

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.