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
  • 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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