ArticleMolecular neurodegeneration2025
Death-associated protein kinase 1-dependent SENP1 degradation increases tau SUMOylation and leads to cognitive dysfunction in a mouse model for tauopathy.
Article in Molecular neurodegeneration, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Selective degradation of DAPK1 via a novel hydrophobic tagging attenuates tau pathology in Alzheimer's disease.Journal of advanced research · 2026Article
- Endothelial miR-15a/16-1 Regulation of SYNE1 Mediates Structural and Functional Recovery after Traumatic Brain Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Development of a Novel AAV-Mediated microRNA Gene Therapy for Spatial Suppression of BACE1 to Improve Cognitive Function in Alzheimer's Disease Model Mice.Biomolecules · 2026Article
- A Novel PROTAC Confers a Dual Benefit Against Amyloid and Tau Pathology in Alzheimer's Disease via DAPK1 Degradation.International journal of biological sciences · 2026Article
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17 authors.
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Abstract
backgroundEmerging evidence implicates that tau SUMOylation disrupts tau homeostasis. Death-associated protein kinase 1 (DAPK1) has been shown to affect tau phosphorylation and accumulation. The sentrin-specific protease 1 (SENP1) is important for protein SUMOylation, and is a potential substrate of DAPK1. However, whether DAPK1 regulates tau SUMOylation and proteostasis through modulating SENP1 remains elusive.
methodsWe identified the phosphorylation of SENP1 by DAPK1 using in vitro kinase assay and mass spectrometry. The influence of DAPK1 on SENP1 expression, tau SUMOylation and phosphorylation was analyzed using a mouse model for tauopathy by overexpressing human tau in the hippocampal CA3 region, as well as using human AD brain tissues. DAPK1 genetic ablation or pharmacological inhibition was applied to assess the impact of DAPK1 on tau accumulation-related pathologies including synaptic dysfunction and gliosis. The cognitive and emotional functions were evaluated using Y-maze, novel object recognition test, Morris water maze, open field test, and elevated plus maze.
resultsDAPK1 directly interacts with and phosphorylates SENP1, leading to SENP1 degradation via the ubiquitin-proteasome pathway. DAPK1 promotes tau SUMOylation by suppressing SENP1 expression in neurons. DAPK1 downregulation or pharmacological inhibition restores SENP1 level and reduces tau SUMOylation, resulting in an attenuation of aberrant tau phosphorylation and accumulation, which ultimately contributes to improved cognitive ability in vivo. We show that DAPK1 expression is negatively correlated with SENP1 level in human AD hippocampal tissues.
conclusionsDAPK1-mediated SENP1 phosphorylation and degradation promote tau SUMOylation, exacerbating tau pathology and cognitive dysfunction in tauopathy. Our findings highlight the DAPK1-SENP1-tau SUMOylation axis as a critical regulator of tau homeostasis, and establish DAPK1 inhibition as a promising therapeutic strategy for AD and related tauopathies.
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