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PSD-93 Interacts with SynGAP and Promotes SynGAP Ubiquitination and Ischemic Brain Injury in Mice
- Source :
- Translational Stroke Research. 11:1137-1147
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 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.
- Subjects :
- 0301 basic medicine
biology
business.industry
General Neuroscience
Central nervous system
Ischemia
Neurotoxicity
medicine.disease
Cell biology
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
medicine.anatomical_structure
nervous system
Ubiquitin
Knockout mouse
Synaptic plasticity
medicine
biology.protein
NMDA receptor
Neurology (clinical)
Cardiology and Cardiovascular Medicine
business
Postsynaptic density
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 1868601X and 18684483
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Translational Stroke Research
- Accession number :
- edsair.doi...........6aa0c4b410c5bd392b9c1be4f55b1403