Neuronal-specific TNFAIP1 ablation attenuates postoperative cognitive dysfunction via targeting SNAP25 for K48-linked ubiquitination.

Wei Wang, Wenwei Gao, Ping Gong, Wenqin Song, Xueshan Bu, Jiabao Hou, Lei Zhang, Bo Zhao

Cell communication and signaling : CCS 2023 Dec 15

filter terms:

Synaptosomal-associated protein 25 (SNAP25) exerts protective effects against postoperative cognitive dysfunction (POCD) by promoting PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy and repressing caspase-3/gasdermin E (GSDME)-mediated pyroptosis. However, the regulatory mechanisms of SNAP25 protein remain unclear. We employed recombinant adeno-associated virus 9 (AAV9)-hSyn to knockdown tumor necrosis factor α-induced protein 1 (TNFAIP1) or SNAP25 and investigate the role of TNFAIP1 in POCD. Cognitive performance, hippocampal injury, mitophagy, and pyroptosis were assessed. Co-immunoprecipitation (co-IP) and ubiquitination assays were conducted to elucidate the mechanisms by which TNFAIP1 stabilizes SNAP25. Our results demonstrated that the ubiquitin ligase TNFAIP1 was upregulated in the hippocampus of mice following isoflurane (Iso) anesthesia and laparotomy. The N-terminal region (residues 1-96) of TNFAIP1 formed a conjugate with SNAP25, leading to lysine (K) 48-linked polyubiquitination of SNAP25 at K69. Silencing TNFAIP1 enhanced SH-SY5Y cell viability and conferred antioxidant, pro-mitophagy, and anti-pyroptosis properties in response to Iso and lipopolysaccharide (LPS) challenges. Conversely, TNFAIP1 overexpression reduced HT22 cell viability, increased reactive oxygen species (ROS) accumulation, impaired PINK1/Parkin-dependent mitophagy, and induced caspase-3/GSDME-dependent pyroptosis by suppressing SNAP25 expression. Neuron-specific knockdown of TNFAIP1 ameliorated POCD, restored mitophagy, and reduced pyroptosis, which was reversed by SNAP25 depletion. In summary, our findings demonstrated that inhibiting TNFAIP1-mediated degradation of SNAP25 might be a promising therapeutic approach for mitigating postoperative cognitive decline. Video Abstract. © 2023. The Author(s).

Citation

Wei Wang, Wenwei Gao, Ping Gong, Wenqin Song, Xueshan Bu, Jiabao Hou, Lei Zhang, Bo Zhao. Neuronal-specific TNFAIP1 ablation attenuates postoperative cognitive dysfunction via targeting SNAP25 for K48-linked ubiquitination. Cell communication and signaling : CCS. 2023 Dec 15;21(1):356