title: SUMO-specific protease 1 protects neurons from apoptotic death during transient brain ischemia/reperfusion.
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.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Aoxue
authors.initials: A
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Dehua
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Developmental and Behavioral Pediatrics, Shanghai Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Shining
authors.initials: S
authors.lastname: Deng
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jinke
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D000066829:Neuroprotection; D009928:Organ Specificity; D015427:Reperfusion Injury / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism
chemical_list: D025841:Small Ubiquitin-Related Modifier Proteins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C501974:Senp1 protein, mouse