Whole Genome Expression Analysis in a Mouse Model of Tauopathy Identifies MECP2 as a Possible Regulator of Tau Pathology.
Whole Genome Expression Analysis in a Mouse Model of Tauopathy Identifies MECP2 as a Possible Regulator of Tau Pathology.
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DOI：
10.3389/fnmol.2017.00069
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发表时间：
2017
影响因子：
4.8
通讯作者：
Bhaskar K
中科院分区：
文献类型：
--
作者：
Maphis NM;Jiang S;Binder J;Wright C;Gopalan B;Lamb BT;Bhaskar K
越来越多的证据表明，微管相关蛋白tau（MAPT或tau）的过度磷酸化和聚集与阿尔茨海默病（AD）和相关tau蛋白病中认知障碍的发展相关。虽然已经进行了许多尝试来在各种动物模型中对AD相关的tau病理进行建模，但是这些模型在完全重现如在人类tau蛋白病中所见的疾病进展方面的成功非常有限。在此，我们在tau蛋白病的基因组小鼠模型中进行了全基因组基因表达，所述小鼠模型在内源性人MAPT启动子的控制下表达人MAPT基因，并且还完全敲除内源性小鼠tau [称为“hTauMaptKO（杜克）”小鼠]。首先，全基因组表达分析揭示了64个基因，与年龄匹配的非转基因对照相比，这些基因在6个月大的hTauMaptKO（杜克）小鼠的海马中差异表达（32个上调和32个下调）。与神经元功能或神经系统疾病相关的基因包括上调基因：PKC-α（Prkca）、MECP 2（Mecp 2）、STRN 4（Strn 4）、SLC 40 a1（Slc 40 a1）、POLD 2（Pold 2）、PCSK 2（Pcsk 2），以及下调基因：KRT 12（Krt 12）、LASS 1（Cers 1）、PLAT（Plat）和NRXN 1（Nrxn 1）。其次，网络分析表明，与年龄匹配的非转基因对照相比，hTauMaptKO（杜克）小鼠的解剖结构发育、细胞代谢过程、细胞死亡、信号转导和应激反应是显著改变的生物学过程。对一组显著改变基因的进一步表征显示，与年龄匹配的对照组相比，hTauMaptKO（杜克）小鼠中MECP 2（甲基-CpG结合蛋白-2）的磷酸化水平升高，MECP 2与甲基化CpG结合并与染色质结合。第三，与健康对照相比，来自人AD的尸检脑样品中的phoshpho-MECP 2升高。最后，在表达人tau的N2 a细胞中siRNA介导的MECP 2敲低导致总tau和磷酸化tau的显著减少。总之，这些结果表明，MECP 2是与AD和tau蛋白病相关的tau蛋白病的潜在新调节剂。
Increasing evidence suggests that hyperphosphorylation and aggregation of microtubule-associated protein tau (MAPT or tau) correlates with the development of cognitive impairment in Alzheimer’s disease (AD) and related tauopathies. While numerous attempts have been made to model AD-relevant tau pathology in various animal models, there has been very limited success for these models to fully recapitulate the progression of disease as seen in human tauopathies. Here, we performed whole genome gene expression in a genomic mouse model of tauopathy that expressed human MAPT gene under the control of endogenous human MAPT promoter and also were complete knockout for endogenous mouse tau [referred to as ‘hTauMaptKO(Duke)′ mice]. First, whole genome expression analysis revealed 64 genes, which were differentially expressed (32 up-regulated and 32 down-regulated) in the hippocampus of 6-month-old hTauMaptKO(Duke) mice compared to age-matched non-transgenic controls. Genes relevant to neuronal function or neurological disease include up-regulated genes: PKC-alpha (Prkca), MECP2 (Mecp2), STRN4 (Strn4), SLC40a1 (Slc40a1), POLD2 (Pold2), PCSK2 (Pcsk2), and down-regulated genes: KRT12 (Krt12), LASS1 (Cers1), PLAT (Plat), and NRXN1 (Nrxn1). Second, network analysis suggested anatomical structure development, cellular metabolic process, cell death, signal transduction, and stress response were significantly altered biological processes in the hTauMaptKO(Duke) mice as compared to age-matched non-transgenic controls. Further characterization of a sub-group of significantly altered genes revealed elevated phosphorylation of MECP2 (methyl-CpG-binding protein-2), which binds to methylated CpGs and associates with chromatin, in hTauMaptKO(Duke) mice compared to age-matched controls. Third, phoshpho-MECP2 was elevated in autopsy brain samples from human AD compared to healthy controls. Finally, siRNA-mediated knockdown of MECP2 in human tau expressing N2a cells resulted in a significant decrease in total and phosphorylated tau. Together, these results suggest that MECP2 is a potential novel regulator of tau pathology relevant to AD and tauopathies.