PSD-93 Interacts with SynGAP and Promotes SynGAP Ubiquitination and Ischemic Brain Injury in Mice
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ORIGINAL ARTICLE
PSD-93 Interacts with SynGAP and Promotes SynGAP Ubiquitination and Ischemic Brain Injury in Mice Qingxiu Zhang 1 & Hui Yang 2 & Hong Gao 1 & Xiaomei Liu 3 & Qingjie Li 4 & Rong Rong 5 & Zhenqian Liu 1 & Xiu-e Wei 1 & Liping Kong 1 & Yun Xu 5,6,7 & Liangqun Rong 1 Received: 6 January 2020 / Revised: 5 February 2020 / Accepted: 20 February 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Postsynaptic density protein-93 (PSD-93) plays an important role in ischemic brain injury through N-methyl-D-aspartate receptor (NMDAR)–triggered neurotoxicity. GTPase-activating protein for Ras (SynGAP) is a GAP specifically expressed in the central nervous system to regulate nerve development and synaptic plasticity. However, the link between PSD-93 and SynGAP and their role in ischemic brain injury remain elusive. Here, we showed that PSD-93 interacted with SynGAP and mediated SynGAP ubiquitination and degradation following ischemic brain injury. Proteasome inhibitor MG-132 could reverse the decrease of SynGAP protein level in wild-type mice following cerebral ischemia reperfusion through inhibiting SynGAP ubiquitination. Furthermore, NMDA receptor inhibitor MK801 could increase SynGAP protein level in wild-type mice following cerebral ischemia reperfusion. However, in PSD-93 knockout mice, MG-132 or NMDAR inhibitor had no significant effect on SynGAP expression. Both MG-132 and PSD-93 knockout reduced infarct volume and improved neurological deficit in mice at different time points after cerebral ischemia reperfusion. Furthermore, we identified that 670–685 amino acid sequence of SynGAP was essential to the binding of SynGAP to PSD-93, and designed a fusion peptide Tat-SynGAP (670–685aa) that could attenuate ischemic brain damage in wild-type mice. In conclusion, we provide the first evidence that PSD-93 directly interacts with SynGAP and mediates its ubiquitination and degradation to aggravate ischemic brain damage. Tat-SynGAP (670–685aa) may be considered as a candidate for treatment of acute ischemic stroke. Keywords PSD-93 . Neuronal excitotoxicity . SynGAP . Ischemic brain injury . Ubiquitination
Introduction Ischemic stroke is still a major concern in the clinic because of high incidence, high morbidity, and high mortality rates [1, 2]. The cerebral ischemia reperfusion–induced neuronal damage
is a complex process, and the underlying mechanism remains to be elucidated. Release and aggregation of excitatory amino acids are known to activate postsynaptic membrane N-methylD-aspartic acid receptors (N-methyl-D-aspartic acid receptor, NMDAR) through postsynaptic density (PSD) scaffolding
Qingxiu Zhang and Hui Yang contributed equally to this work. * Yun Xu [email protected] * Liangqun Rong [email protected] 1
Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, 32 Coal Road, Xuzhou 221006, Jiangsu, People’s Republic of China
2
Department of Neurosurgery, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuz
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