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<p>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 <i>Caenorhabditis elegans</i> as a model, we found that loss-of-function mutations in <i>pink-1</i> delayed defecation rhythm, resulting in aberrant intestinal colonization upon the pathogenic bacterium <i>Pseudomonas aeruginosa</i> PA14 exposure, which subsequently accelerates dopaminergic neurodegeneration. Mechanistically, PINK-1 in neurons regulated <i>dgk-1</i> expression, a key positive regulator of defecation, through direct binding of the downstream transcription factor CEH-22 in the <i>dgk-1</i> promoter region. Concurrently, <i>pink-1</i> 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 <i>pink-1</i> mutation in the <i>C. elegans</i> 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.</p>

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Tissue-specific mutation of pink-1 jointly induces intestinal dysfunction and contributes to dopaminergic neuron degeneration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月16日

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  • Huan Gu,
  • Yixin Li,
  • Guolin Shi,
  • Wenhui Zhou,
  • Yi Dou,
  • Wenhu Li,
  • Jian Pu,
  • Yanmei Su,
  • Ninghui Zhao,
  • Xiaowei Huang

摘要

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.