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

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

  • Cell Commun Signal. 2023 Dec 15;21(1):356. doi: 10.1186/s12964-023-01390-z.
Wei Wang # 1,  Wenwei Gao # 2,  Ping Gong # 1 3,  Wenqin Song 1,  Xueshan Bu 1,  Jiabao Hou 1,  Lei Zhang 4,  Bo Zhao 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuhan, 430060, China.
  • 2 Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 3 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, Department of Anesthesiology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
  • 4 Department of Anesthesiology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuhan, 430060, China. zl21st@163.com.
  • 5 Department of Anesthesiology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuhan, 430060, China. zb14526@163.com.
  • # Contributed equally.
PMID: 38102610 DOI: 10.1186/s12964-023-01390-z
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Mitophagy; Postoperative cognitive dysfunction; Pyroptosis; SNAP25; TNFAIP1; Ubiquitination.

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