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

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 dysmoti

SUBMITTER: Mu C 

PROVIDER: S-EPMC12663421 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature