Neuroprotective Effect of E3 Ubiquitin Ligase RNF8 Against Ischemic Stroke via HDAC2 Stability Reduction and Reelin-Dependent GSK3β Inhibition

Loss of E3 ubiquitin ligase RING finger protein 8 (RNF8) may lead to neuronal DNA damage and apoptosis. In order to expand on our knowledge on the mechanistic basis underlying neuronal death in ischemic stroke, the present study sought to investigate the potential role of E3 ubiquitin ligase RNF8 on ischemic stroke and explore the underlying downstream mechanism. Middle cerebral artery occlusion (MCAO) in mice and oxygen–glucose deprivation/reoxygenation (OGD/R) in neurons were induced to simulate an ischemic stroke environment. It was found that downregulation of RNF8 and Reelin occurred in MCAO mice and OGD/R-exposed neurons. Silencing of RNF8 enhanced the MCAO-induced neuronal apoptosis and oxidative stress. Mechanistically, RNF8 enhanced the ubiquitination and degradation of HDAC2, thus attenuating OGD/R-induced neuronal apoptosis and oxidative stress. Moreover, HDAC2 inhibited Reelin expression through deacetylation of H3K27me3 in its promoter, causing reduced glycogen synthase kinase-3beta (GSK3β)-Ser9 phosphorylation and the resultant elevated GSK3β activity. By this mechanism, RNF8 alleviated ischemic stroke. Coherently, this study suggests that RNF8 plays a neuroprotective effect against ischemic stroke by downregulating HDAC2 expression and inducing Reelin-induced GSK3β inhibition. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-022-02880-w.