2. Academic Validation
  3. LAMP2A-mediated neuronal hyperexcitability by enhancing NKAβ1 degradation underlies depression-induced allodynia

LAMP2A-mediated neuronal hyperexcitability by enhancing NKAβ1 degradation underlies depression-induced allodynia

  • Cell Rep. 2025 Apr 22;44(4):115489. doi: 10.1016/j.celrep.2025.115489.
Yuxin Zhang 1,  Huanghui Wu 1,  Qian Zhang 1,  Peilin Cong 1,  Zhouxiang Li 1,  Qianqian Wu 1,  Xinwei Huang 1,  Xinyang Li 1,  Ban Feng 1,  Qiong Liu 2,  Lize Xiong 3
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 2 Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: liuqiong8001@hotmail.com.
  • 3 Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: mzkxlz@126.com.
PMID: 40178973 DOI: 10.1016/j.celrep.2025.115489
Abstract

Painful physical symptoms in major depressive disorder (MDD) patients lead to poor outcomes during MDD treatment. Here, we report that decreased Na+/K+-ATPase β1 subunit (NKAβ1) expression in anterior cingulate cortex glutamatergic (ACCGlu) neurons promotes ion dyshomeostasis, leading to hyperactivity of ACCGlu-insular cortex circuits in chronic stress mice. This ultimately primes allodynia. Mechanistically, we reveal that chronic stress strengthens LAMP2A-driven chaperone-mediated Autophagy (CMA) and subsequently promotes the degradation of NKAβ1. We further identify NKAβ1 as a CMA substrate. Accordingly, genetically LAMP2A loss in ACCGlu neurons reverses chronic-stress-induced neuronal hyperexcitability, subsequently ameliorating allodynia. Additionally, we develop a trans-activating transcription (TAT)-LAMP2A peptide that significantly alleviates depression-induced allodynia. Taken together, our results reveal a mechanistic connection between CMA and neuronal excitability. TAT-LAMP2A peptide intervention, by disturbing CMA-dependent NKAβ1 elimination, could be a potential pharmacological treatment for depression-induced allodynia and further facilitate the efficacy of antidepressant treatment.

Keywords

CP: Molecular biology; CP: Neuroscience; LAMP2A; NKAβ1; allodynia; anterior cingulate cortex; depression.

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