In C. elegans, tissue-specific loss of pink-1 causes neuronal dysregulation of dgk-1 that impairs defecation rhythm and intestinal pink-1 loss that suppresses glutathione metabolism, together promoting pathogenic gut colonization and ROS-driven dopaminergic neurodegeneration, with aspects conserved…

By linking PINK1 to gut-brain interactions, glutathione-dependent redox failure, and a defined neuronal transcriptional pathway, this study reveals actionable targets (antioxidant/glutathione pathways, gut microbial control, and DGK-related signaling) for therapeutic exploration in PD despite the…

In patients with Parkinson's disease (PD), intestinal dysfunction represents one of the predominant non-motor symptoms and typically manifests at the earliest stages of the disease. However, the underlying causes of intestinal dysfunction and its impact on disease progression remain to be fully elucidated. Using Caenorhabditis elegans as a model, we found that loss-of-function mutations in pink-1 delayed defecation rhythm, resulting in aberrant intestinal colonization upon the pathogenic bacterium Pseudomonas aeruginosa PA14 exposure, which subsequently accelerates dopaminergic neurodegeneration. Mechanistically, PINK-1 in neurons regulated dgk-1 expression, a key positive regulator of defecation, through direct binding of the downstream transcription factor CEH-22 in the dgk-1 promoter region. Concurrently, pink-1 mutation in the intestine suppresses the glutathione metabolic pathway and impairs the clearance of reactive oxygen species (ROS) induced by pathogenic accumulation. Notably, the regulatory role of PINK-1 is evolutionarily conserved in mammalian cells. Our findings demonstrate that pink-1 mutation in the C. elegans model exhibits the constipation phenotype similar to that observed in early-stage PD patients and weakens resistance to microbial infections via inactivating glutathione metabolic pathway. These results clarify a causal link between intestinal dysfunction and neurodegeneration, providing novel insights into the role of PINK-1 in PD pathogenesis.