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<p>Constipation and depression are prevalent non-motor symptoms (NMS) of Parkinson’s disease (PD) that often co-occur, yet their shared pathophysiology remains unclear. Here, we identify enteric glial cells (EGCs) as central regulators of the gut–brain axis, wherein aberrant activation of the TLR4/NEDD4/CX43 signaling axis drives sustained ATP release, impairing serotonin (5-HT) synthesis in enterochromaffin (EC) cells. This ATP-mediated purinergic toxicity provides a unifying molecular mechanism for PD-associated constipation and depression (PD-CD). Mechanistically, TLR4 activation promotes TRAF6-dependent ubiquitination and degradation of NEDD4, reducing CX43 clearance. CX43 accumulation at the plasma membrane enhances ATP release, suppressing EC-derived 5-HT and contributing to gut dysmotility and mood disturbances. Critically, glial cell–derived neurotrophic factor (GDNF) stabilizes NEDD4 via the Ret–Src pathway, restores CX43 ubiquitination, limits ATP leakage, and rescues 5-HT synthesis, alleviating constipation and depressive phenotypes in PD mice. The probiotic <i>Akkermansia muciniphila</i> Akk11 (Akk11) similarly induces endogenous GDNF, producing comparable protective effects. Together, these findings establish an “EGC–EC axis” model for PD-CD and highlight GDNF-centered interventions as a promising multi-target strategy for PD NMS.</p>

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GDNF signaling modulation by Akkermansia muciniphila ameliorates constipation–depression comorbidity in Parkinson’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • Chunyan Mu,
  • Zairen Zhou,
  • Jingyu Li,
  • Mingyu Su,
  • Ke Xue,
  • Jingyuan Zhang,
  • Shijie Shi,
  • Ye Li,
  • Xiaoyu Yao,
  • Mengxue Wang,
  • Wanxiang Zhang,
  • Zhe Wang,
  • Jianguo Zhu,
  • Shuguang Fang,
  • Wei Wang,
  • Chuanxi Tang,
  • Xiaoling Qin

摘要

Constipation and depression are prevalent non-motor symptoms (NMS) of Parkinson’s disease (PD) that often co-occur, yet their shared pathophysiology remains unclear. Here, we identify enteric glial cells (EGCs) as central regulators of the gut–brain axis, wherein aberrant activation of the TLR4/NEDD4/CX43 signaling axis drives sustained ATP release, impairing serotonin (5-HT) synthesis in enterochromaffin (EC) cells. This ATP-mediated purinergic toxicity provides a unifying molecular mechanism for PD-associated constipation and depression (PD-CD). Mechanistically, TLR4 activation promotes TRAF6-dependent ubiquitination and degradation of NEDD4, reducing CX43 clearance. CX43 accumulation at the plasma membrane enhances ATP release, suppressing EC-derived 5-HT and contributing to gut dysmotility and mood disturbances. Critically, glial cell–derived neurotrophic factor (GDNF) stabilizes NEDD4 via the Ret–Src pathway, restores CX43 ubiquitination, limits ATP leakage, and rescues 5-HT synthesis, alleviating constipation and depressive phenotypes in PD mice. The probiotic Akkermansia muciniphila Akk11 (Akk11) similarly induces endogenous GDNF, producing comparable protective effects. Together, these findings establish an “EGC–EC axis” model for PD-CD and highlight GDNF-centered interventions as a promising multi-target strategy for PD NMS.