2. Academic Validation
  3. GDNF signaling modulation by Akkermansia muciniphila ameliorates constipation-depression comorbidity in Parkinson's disease

GDNF signaling modulation by Akkermansia muciniphila ameliorates constipation-depression comorbidity in Parkinson's disease

  • NPJ Parkinsons Dis. 2025 Nov 28;11(1):342. doi: 10.1038/s41531-025-01190-x.
Chunyan Mu # 1 2 3,  Zairen Zhou # 4,  Jingyu Li 3 5,  Mingyu Su 3 6,  Ke Xue 3,  Jingyuan Zhang 3,  Shijie Shi 3,  Ye Li 3,  Xiaoyu Yao 3,  Mengxue Wang 5,  Wanxiang Zhang 6,  Zhe Wang 7,  Jianguo Zhu 7,  Shuguang Fang 7,  Wei Wang 8 9,  Chuanxi Tang 10,  Xiaoling Qin 11
Affiliations

Affiliations

  • 1 Department of Neurology, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China.
  • 2 Xuzhou Dongfang People's Hospital, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 3 Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 4 Institute of Science and Technology for Brain-lnspired intelligence, Fudan University, Shanghai, China.
  • 5 The Second Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 6 School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 7 Department of Research and Development, Wecare Probiotics Co. Ltd., Suzhou, China.
  • 8 Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. [email protected].
  • 9 The Second Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, China. [email protected].
  • 10 Department of Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. [email protected].
  • 11 Department of Neurology, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41315295 DOI: 10.1038/s41531-025-01190-x
Abstract

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.

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