From the Department of Pathology and Experimental Therapeutics, University of Barcelona, Barcelona, Spain.
CIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases), Institute of Health Carlos III, Barcelona, Spain.
J Neuropathol Exp Neurol. 2022 Aug 16;81(9):696-706. doi: 10.1093/jnen/nlac062.
The neocortex of P301S mice, used as a model of fronto-temporal lobar degeneration linked to tau mutation (FTLD-tau), and wild-type mice, both aged 9 months, were analyzed with conventional label-free phosphoproteomics and SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) to assess the (phospho)proteomes. The total number of identified dysregulated phosphoproteins was 328 corresponding to 524 phosphorylation sites. The majority of dysregulated phosphoproteins, most of them hyperphosphorylated, were proteins of the membranes, synapses, membrane trafficking, membrane vesicles linked to endo- and exocytosis, cytoplasmic vesicles, and cytoskeleton. Another group was composed of kinases. In contrast, proteins linked to DNA, RNA metabolism, RNA splicing, and protein synthesis were hypophosphorylated. Other pathways modulating energy metabolism, cell signaling, Golgi apparatus, carbohydrates, and lipids are also targets of dysregulated protein phosphorylation in P301S mice. The present results, together with accompanying immunohistochemical and Western-blotting studies, show widespread abnormal phosphorylation of proteins, in addition to protein tau, in P301S mice. These observations point to dysregulated protein phosphorylation as a relevant contributory pathogenic component of tauopathies.
P301S 小鼠的大脑新皮层被用作与 tau 突变相关的额颞叶退行性变（FTLD-tau）的模型，以及野生型小鼠，两者均为 9 个月大，使用常规无标记磷酸化蛋白质组学和 SWATH-MS（所有理论片段离子谱质谱的顺序窗口采集）进行分析，以评估（磷酸化）蛋白质组。鉴定出的失调磷酸化蛋白总数为 328 个，对应于 524 个磷酸化位点。大多数失调的磷酸化蛋白，其中大多数是过度磷酸化的，是膜、突触、膜运输、与内吞作用和胞吐作用相关的膜囊泡、细胞质囊泡和细胞骨架的蛋白质。另一组由激酶组成。相比之下，与 DNA、RNA 代谢、RNA 剪接和蛋白质合成相关的蛋白质被低磷酸化。其他调节能量代谢、细胞信号转导、高尔基器、碳水化合物和脂质的途径也是 P301S 小鼠失调蛋白磷酸化的靶点。目前的结果，连同伴随的免疫组织化学和 Western-blotting 研究，显示 P301S 小鼠中除了蛋白 tau 之外，还有广泛的异常蛋白磷酸化。这些观察结果表明，蛋白磷酸化失调是 tau 病的一个相关致病成分。
