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<p>Chronic intestinal inflammation is a key precursor to Parkinson’s disease (PD). Leucine-rich repeat kinase 2 R1628P variant (LRRK2<sup>R1628P</sup>) is a risk factor for PD in Asians. However, whether it drives the occurrence of intestinal inflammation remains elusive. Here, we report that LRRK2<sup>R1627P</sup> (the rat homolog) disrupts intestinal homeostasis during aging and toxin exposure in rats. Compared with age-matched wild-type rats, aging LRRK2<sup>R1627P</sup> rats exhibited shortened small intestine, reduced goblet cells, and abnormal epithelial cell junction structures. Mechanistically, these changes were induced by macrophage polarization toward a pro-inflammatory phenotype via TLR4/MyD88/NF-κB pathway, resulting in PD-associated intestinal pathology, including chronic inflammatory, decreased microbial diversity, and increased p-α-synuclein aggregation. LRRK2<sup>R1627P</sup> also enhanced susceptibility to lipopolysaccharide-induced intestinal inflammation. Remarkably, TLR4 inhibitor ameliorated the age-related disruption of intestinal homeostasis mediated by LRRK2<sup>R1627P</sup>. Using the LRRK2<sup>R1627P</sup> rats, this study reveals a cascading interplay among genetic susceptibility, age-related internal imbalance, and exogenous toxin exposure in PD pathology. These findings provide critical insights into how the dynamic interplay of multiple risk factors overwhelms the body’s compensatory thresholds, ultimately initiating the pathological process of neurodegeneration.</p><p></p>

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LRRK2R1627P mutation amplifies environmental risk factors induced chronic inflammation and α-synuclein aggregation in the gut of rats

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月7日

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  • Shimin Pang,
  • Jing Lu,
  • Yanyan Wang,
  • Chao Ying,
  • Chunsong Zhao,
  • Zhenyu Yue,
  • Qiumei Yang,
  • Piu Chan

摘要

Chronic intestinal inflammation is a key precursor to Parkinson’s disease (PD). Leucine-rich repeat kinase 2 R1628P variant (LRRK2R1628P) is a risk factor for PD in Asians. However, whether it drives the occurrence of intestinal inflammation remains elusive. Here, we report that LRRK2R1627P (the rat homolog) disrupts intestinal homeostasis during aging and toxin exposure in rats. Compared with age-matched wild-type rats, aging LRRK2R1627P rats exhibited shortened small intestine, reduced goblet cells, and abnormal epithelial cell junction structures. Mechanistically, these changes were induced by macrophage polarization toward a pro-inflammatory phenotype via TLR4/MyD88/NF-κB pathway, resulting in PD-associated intestinal pathology, including chronic inflammatory, decreased microbial diversity, and increased p-α-synuclein aggregation. LRRK2R1627P also enhanced susceptibility to lipopolysaccharide-induced intestinal inflammation. Remarkably, TLR4 inhibitor ameliorated the age-related disruption of intestinal homeostasis mediated by LRRK2R1627P. Using the LRRK2R1627P rats, this study reveals a cascading interplay among genetic susceptibility, age-related internal imbalance, and exogenous toxin exposure in PD pathology. These findings provide critical insights into how the dynamic interplay of multiple risk factors overwhelms the body’s compensatory thresholds, ultimately initiating the pathological process of neurodegeneration.