PSD-93 Interacts with SynGAP and Promotes SynGAP Ubiquitination and Ischemic Brain Injury in Mice
- 4 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Translational Stroke Research
- Vol. 11 (5), 1137-1147
- https://doi.org/10.1007/s12975-020-00795-z
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
Funding Information
- The National Natural Science Foundation of China (81671149 and 81301120, 81971179)
- the Natural Science Foundation of of Jiangsu Province (BK20161167)
- the Natural Science Foundation of of Jiangsu Province (BK20151168)
- the Natural Science Foundation of the Colleges and Universities in Jiangsu Province (13KJB320027)
- the Xuzhou Medical Young Talents Project (-)
- The Natural Science Foundation of Jiangsu Province (BK20191463)
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