ArticleTranslational neurodegeneration2024
Neuronal double-stranded DNA accumulation induced by DNase II deficiency drives tau phosphorylation and neurodegeneration.
Article in Translational neurodegeneration, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review).Experimental and therapeutic medicine · 2026Review
- NDST3 suppression restores lysosomal acidification and ameliorates amyloid-β and MAPT/tau pathology in Alzheimer's disease.Translational neurodegeneration · 2026Article
- Cerebrospinal Fluid Proteome Reveals Dysregulation of Lysosomal and Axonal Proteins in Neurosyphilis.Journal of proteome research · 2026Article
- Porous Baicalin-Fe(III) ICP@Propofol nanocomposites for enhanced anesthetic efficacy and reduced toxicity via neuroprotection and ultrasound assistance.Asian journal of pharmaceutical sciences · 2026Article
- From uric acid to tophi: multistage molecular and cellular mechanisms of tophi formation.Frontiers in immunology · 2026Review
- Cell-free DNA in sepsis: from molecular insights to clinical management.Military Medical Research · 2025Review
- Review
- Telomere-driven senescence accelerates tau pathology, neuroinflammation and neurodegeneration in a tauopathy mouse model.Acta neuropathologica communications · 2025Article
- Reversing Persistent PTEN Activation after Traumatic Brain Injury Fuels Long-Term Axonal Regeneration via Akt/mTORC1 Signaling Cascade.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Microglial double stranded DNA accumulation induced by DNase II deficiency drives neuroinflammation and neurodegeneration.Journal of neuroinflammation · 2025Article
- Role of Calmodulin in Neurodegeneration and Neuroprotection.Mini reviews in medicinal chemistry · 2025Review
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15 authors.
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Abstract
backgroundDeoxyribonuclease 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.
methodsThe 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.
resultsThe levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits.
conclusionsDNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders.
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