SUMO-specific protease 1 protects neurons from apoptotic death during transient brain ischemia/reperfusion

• Published in: Cell death & disease Vol. 7; no. 11; p. e2484
• Main Authors: Zhang, Huijun, Wang, Yan, Zhu, Aoxue, Huang, Dehua, Deng, Shining, Cheng, Jinke, Zhu, Michael X, Li, Yong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.11.2016; Springer Nature B.V; Nature Publishing Group
• Subjects: 14/19; 14/63; 42/109; 631/443/592/75/593/1370/534; 631/45/474/538; 631/45/607/468; 631/80/82/23; 82/51; 96/2; Animals; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Brain Ischemia - complications; Brain Ischemia - pathology; Cell Biology; Cell Culture; Cerebral Cortex - pathology; Cerebral Cortex - physiopathology; Endopeptidases - deficiency; Endopeptidases - metabolism; Immunology; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - physiopathology; Life Sciences; Male; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Neurons - metabolism; Neurons - pathology; Neuroprotection; Organ Specificity; Original; original-article; Reperfusion Injury - complications; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; Small Ubiquitin-Related Modifier Proteins - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2016.290

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 SENP1 flox/flox :CamKII α -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.