Abstract
BACKGROUND: Emerging 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. METHODS: We 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. RESULTS: DAPK1 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. CONCLUSIONS: DAPK1-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.