Abstract
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. Here we show that transient middle cerebral artery occlusion in mice followed by 6, 12 and 24 h reperfusion significantly enhanced SENP1 levels in the affected brain area, independent of transcription. Consistent with the increase in SENP1, the levels of SUMO1-conjugated proteins were decreased by I/R in cortical neurons of control littermate mice, but unchanged in that of animals with conditional ablation of SENP1 gene from adult principal neurons, the SENP1flox/flox:CamKIIα-Cre (SENP1 cKO) mice. The SENP1 cKO mice exhibited a significant increase in infarct volume in the cerebral cortex and more severe motor impairment in response to I/R as compared with the control littermates. Cortical neurons from I/R-injured SENP1 cKO mice became more apoptotic than that from control littermates, as indicated by both TUNEL staining and caspase-3 activation. Overexpression of SENP1 in somatosensory cortices of adult wild-type (WT) mice suppressed I/R-induced neuronal apoptosis. We conclude that SENP1 plays a neuroprotective role in I/R injury by inhibiting apoptosis through decreasing SUMO1 conjugation. These findings reveal a novel mechanism of neuroprotection by protein desumoylation, which may help develop new therapies for mitigating brain injury associated with ischemic stroke.
Highlights
Sumoylation is a post-translational modification that modifies the interaction of target proteins with protein partners and thereby alters their subcellular localization, activity and stability
To evaluate the role of SENP1 in neuronal damage following brain ischemia and reperfusion (I/R), we first examined the expression of SENP1 in major brain areas of C57BL/6 mice, including cerebellum, cortex and hippocampus
With 40 min transient middle cerebral artery occlusion (tMCAO) followed by a reperfusion for 0, 6, 12 or 24 h, as outlined in Figure 1b, a large area of brain infarction developed in the ipsilateral hemisphere, which was detected by straining brain sections with 2,3,5-triphenyltetrazolium chloride (TTC; Figure 1b, right)
Summary
Sumoylation is a post-translational modification that modifies the interaction of target proteins with protein partners and thereby alters their subcellular localization, activity and stability. A number of studies have shown increased SUMO conjugation of proteins in the brain of animal models of cerebral ischemia/stroke.[4,5,6] This suggests that protein sumoylation may play a role in determining the fate of post-ischemic neurons. In cultured hippocampal neurons subject to in vitro oxygen and glucose deprivation (OGD) treatment, the levels of SUMO-conjugated proteins and the expression of SENP1 were increased, suggesting that the neuronal response to OGD may involve changes in both sumoylation and desumoylation.[3] In addition, a blockade of SUMO2/3 translation in primary cortical neurons enhanced vulnerability to the OGD-induced damage, indicating that SUMO2/3 conjugation may be protective to neuronal injury.[8] sumoylation appeared to exert a role in ischemic preconditioning, an intrinsic process in which repeated short subtoxic episodes of ischemia protect against a subsequent major ischemic insult. Our results reveal an unexpected protective role of neuronal SENP1 in ischemia followed by reperfusion, which should inform new strategies for neuroprotection in ischemic stroke
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
