Shank3 ameliorates neuronal injury after cerebral ischemia/reperfusion via inhibiting oxidative stress and inflammation

Redox Biol. 2024 Feb:69:102983. doi: 10.1016/j.redox.2023.102983. Epub 2023 Dec 5.

Abstract

Shank3, a key molecule related to the development and deterioration of autism, has recently been found to downregulate in the murine brain after ischemia/reperfusion (I/R). Despite this discovery, however, its effects on neuronal injury and the mechanism underlying the effects remain to be clarified. To address this, in this study, based on genetically modified mice models, we revealed that the expression of Shank3 showed a time-dependent change in murine hippocampal neurons after I/R, and that conditional knockout (cko) of Shank3 in neurons resulted in aggravated neuronal injuries. The protective effects of Shank3 against oxidative stress and inflammation after I/R were achieved through direct binding STIM1 and subsequent proteasome-mediated degradation of STIM1. The STIM1 downregulation induced the phosphorylation of downstream Nrf2 Ser40, which subsequently translocated to the nucleus, and further increased the expression of antioxidant genes such as NQO1 and HO-1 in HT22 cells. In vivo, the study has further confirmed that double knockout of Shank3 and Stim1 alleviated oxidative stress and inflammation after I/R in Shank3cko mice. In conclusion, the present study has demonstrated that Shank3 interacts with STIM1 and inhibits post-I/R neuronal oxidative stress and inflammatory response via the Nrf2 pathway. This interaction can potentially contribute to the development of a promising method for I/R treatment.

Keywords: Inflammation; Ischemia/reperfusion injury; Oxidative stress; STIM1; Shank3.

MeSH terms

  • Animals
  • Apoptosis
  • Brain Ischemia* / genetics
  • Brain Ischemia* / metabolism
  • Inflammation / genetics
  • Inflammation / metabolism
  • Mice
  • Microfilament Proteins / metabolism
  • Microfilament Proteins / pharmacology
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Oxidative Stress
  • Reperfusion
  • Reperfusion Injury* / genetics
  • Reperfusion Injury* / metabolism

Substances

  • NF-E2-Related Factor 2
  • Shank3 protein, mouse
  • Microfilament Proteins
  • Nerve Tissue Proteins