Neuronal double-stranded DNA accumulation induced by DNase II deficiency drives tau phosphorylation and neurodegeneration

作者：Ling-Jie Li, Xiaoying Sun, Yaru Huang, Shuai Lü, Yuming Xu, Jing Yang, Xi-xiu Xie, Jie Zhu, Xiaoyun Niu, Dan Wang, Shiyu Liang, Xiaoyu Du, Shengjie Hou, Xiaolin Yu, Rui‐tian Liu · 发表于：Translational Neurodegeneration · 年份：2024 · DOI：10.1186/s40035-024-00427-8 · 被引用次数：14 · 研究领域：Alzheimer's disease research and treatments、DNA Repair Mechanisms、Telomeres, Telomerase, and Senescence

Abstract Background Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer’s disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified. Methods The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test. Results The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently ...