心境障碍可能加速多脏器衰老，但机制不详。前期已发表文章证实端粒特异性保护蛋白TRF2抑制端粒和围着丝粒的DNA损伤，调控神经特异性磷酸酶PP2A调节亚基PPP2R2C表达。预实验建立了PPP2R2C突变斑马鱼模型，证实心境障碍加速系统性衰老，本项目拟：①激光片层扫描、免疫荧光等研究脑组织衰老是否明显早于其他脏器；②酵母双杂交、PLA等证明PPP2R2C和TRF2直接相互作用。DNA损伤阻断剂、杂交ATM敲除鱼获双突变鱼证实PPP2R2C是否调控特定DNA损伤通路。Chip-Seq和3D-FISH等证明PPP2R2C受TRF2招募结合至染色体脆性位点，以PP2A磷酸酶活性抑制DNA损伤。③结合Chip-Seq和RNA-Seq结果筛选PPP2R2C直接调控神经-体循环轴动态平衡，抑制衰老前体因子释放的全新通路。我们将揭示心境障碍加速机体老化的机制，神经精神疾病与个体衰老之间存在共同生物学途径。

Mental disorder may accelerate multiple-organ aging, but the mechanism is unknown. Our previous studies have confirmed that telomere-specific protective protein TRF2 inhibits DNA damage at telomeres and pericentromeres. TRF2 regulates the expression of PPP2R2C, a subunit neurospecific regulatory isoform of phosphatase PP2A. Our pre-experiment established a PPP2R2C mutated zebrafish model and showed that mental disorder accelerates systemic aging. This project is to study: 1) To identify cellular senescence at brain is much earlier than other organs by Light Sheet confocal scanning and immunofluorescence; 2) To measure the direct interaction between PPP2R2C and TRF2 by Yeast two-hybridization and PLA （Proximity Ligation Assay）. Crossing ATM knockout fish with PPP2R2C mutated fish as well as adding DNA damage blockers to confirm that PPP2R2C regulates the specific pathway of DNA damage machinery. Chip-Seq and immunofluorescence will find that PPP2R2C can be recruited by TRF2 to chromosome fragile sites. PPP2R2C can inhibit DNA damage and rescue neural cell senescence by its PP2A phosphatase activity.3) Based on Chip-Seq and RNA-Seq results to discover a new pathway which is PPP2R2C directly regulate the factors that migrate between brain and general circulation transmission to control systemic aging. This project will reveal a common biological pathway between neuropsychiatric diseases and aging.