Neurologic Diseases and Neurogenetics Group, Bellvitge Institute for Biomedical Research (IDIBELL), 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
CIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases), Institute of Health Carlos III, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Int J Mol Sci. 2023 Mar 31;24(7):6559. doi: 10.3390/ijms24076559.
Transcriptomics and phosphoproteomics were carried out in the cerebral cortex of (tau knockout: tau-KO) and wild-type (WT) 12 month-old mice to learn about the effects of tau ablation. Compared with WT mice, tau-KO mice displayed reduced anxiety-like behavior and lower fear expression induced by aversive conditioning, whereas recognition memory remained unaltered. Cortical transcriptomic analysis revealed 69 downregulated and 105 upregulated genes in tau-KO mice, corresponding to synaptic structures, neuron cytoskeleton and transport, and extracellular matrix components. RT-qPCR validated increased mRNA levels of , , , , , , , , , and an absence of in tau-KO mice compared with WT mice. A few proteins were assessed with Western blotting to compare mRNA expression with corresponding protein levels. mRNA and protein levels decreased. However, β-tubulin III and GAD1 protein levels were reduced in tau-KO mice. Cortical phosphoproteomics revealed 121 hypophosphorylated and 98 hyperphosphorylated proteins in tau-KO mice. Deregulated phosphoproteins were categorized into cytoskeletal ( = 45) and membrane proteins, including proteins of the synapses and vesicles, myelin proteins, and proteins linked to membrane transport and ion channels ( = 84), proteins related to DNA and RNA metabolism ( = 36), proteins connected to the ubiquitin-proteasome system (UPS) ( = 7), proteins with kinase or phosphatase activity ( = 21), and 22 other proteins related to variegated pathways such as metabolic pathways, growth factors, or mitochondrial function or structure. The present observations reveal a complex altered brain transcriptome and phosphoproteome in tau-KO mice with only mild behavioral alterations.
在（tau 敲除：tau-KO）和野生型（WT）12 月龄小鼠的大脑皮层中进行了转录组学和磷酸化蛋白质组学研究，以了解 tau 缺失的影响。与 WT 小鼠相比，tau-KO 小鼠表现出较低的焦虑样行为和由厌恶条件引起的较低的恐惧表达，而识别记忆保持不变。皮层转录组分析显示 tau-KO 小鼠中有 69 个下调基因和 105 个上调基因，对应于突触结构、神经元细胞骨架和运输以及细胞外基质成分。实时定量 PCR 验证了与 WT 小鼠相比，tau-KO 小鼠中 、 、 、 、 、 、 、 和 基因的 mRNA 水平增加，而 基因缺失。用 Western blot 法评估了一些蛋白质，以比较 mRNA 表达与相应的蛋白水平。tau-KO 小鼠中 、 、 、 和 的 mRNA 和蛋白水平降低。然而，tau-KO 小鼠中 β-微管蛋白 III 和 GAD1 蛋白水平降低。皮层磷酸化蛋白质组学显示 tau-KO 小鼠中有 121 个低磷酸化蛋白和 98 个高磷酸化蛋白。失调的磷酸化蛋白分为细胞骨架（=45）和膜蛋白，包括突触和囊泡蛋白、髓鞘蛋白以及与膜运输和离子通道相关的蛋白（=84）、与 DNA 和 RNA 代谢相关的蛋白（=36）、与泛素-蛋白酶体系统（UPS）相关的蛋白（=7）、具有激酶或磷酸酶活性的蛋白（=21）以及 22 种与代谢途径、生长因子或线粒体功能或结构等多种途径相关的其他蛋白。本研究结果显示，tau-KO 小鼠仅有轻微的行为改变，但大脑转录组和磷酸化蛋白质组发生了复杂的改变。
