The Role Of SUMO-Specific Protease 1 (SENP1) In Brain Ischemia/Reperfusion Injury

Ischemic stroke is one of the diseases that have the highest incidence,mortality and disability rates,although the current clinical treatment for ischemic stroke is to restore the blood flow to the affected area through thrombolytic therapy,therapeutic options for acute cerebral I/R injury are still limited,suggesting that researches on I/R injury mechanism are very essential.SUMO-specific protease 1（SENP1）deconjugates SUMO from modified proteins.Although post-ischemic activation of SUMO conjugation was suggested to be neuroprotective against ischemia/reperfusion（I/R）injury,the function of SENP1 in this process remained unclear.The present study focuses on uncovering the role of SENP1 in I/R injury which will aid the design of new strategies for preventive and therapeutic interventions in clinically relevant pathological states associated with ischemic stroke.Taking advantage of Immunohistochemistry,biochemistry,behavior test and electrophysiology,we show that transient middle cerebral artery occlusion（tMCAO）in mice followed by 6,12 and 24 h reperfusion significantly enhanced SENP1 levels in the affected brain area,independent of transcription.Conditional ablation of SENP1gene in principal neurons of adult mice,using a SENP1^flox/flox;CamKII-cre（SENP1cKO）line,resulted in a significant increase in infarct volume in cerebral cortex and more severe motor impairment in response to I/R as compared to the wild type littermates.Cortical neurons from I/R-injured SENP1 cKO mice became more apoptotic than wild type neurons,as indicated by both TUNEL staining and caspase3activation.Moreover,consistent with the increase in SENP1 levels,I/R induced an overall decrease in SUMO1-conjugation of cortical neuron proteins including the pro-apoptotic protein,dynamin-related protein 1（Drp1）,and a decrease in Drp1 protein level.We report here that SENP1 plays a neuroprotective role in I/R injury by inhibiting apoptosis through decreasing SUMO1 conjugation and destabilization of Drp1.These findings reveal a novel mechanism of neuroprotection by protein desumoylation,which may have important implications for stroke therapy.