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

  • NPJ Parkinsons Dis. 2026 Feb 7;12(1):68. doi: 10.1038/s41531-026-01281-3.
Shimin Pang  1 ,  Jing Lu  1  2 ,  Yanyan Wang  1 ,  Chao Ying  1 ,  Chunsong Zhao  1 ,  Zhenyu Yue  3 ,  Qiumei Yang  4  5 ,  Piu Chan  6  7  8  9
Affiliations
  • 1. Department of Neurobiology and National Clinical Research Center for Geriatric Disease, Xuanwu Hospital of Capital Medical University, Beijing Institute of Geriatrics, Beijing, China.
  • 2. Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.
  • 3. Department of Neurobiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4. Department of Neurobiology and National Clinical Research Center for Geriatric Disease, Xuanwu Hospital of Capital Medical University, Beijing Institute of Geriatrics, Beijing, China. [email protected].
  • 5. Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China. [email protected].
  • 6. Department of Neurobiology and National Clinical Research Center for Geriatric Disease, Xuanwu Hospital of Capital Medical University, Beijing Institute of Geriatrics, Beijing, China. [email protected].
  • 7. Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China. [email protected].
  • 8. Clinical and Research Center for Parkinson's Disease, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory for Parkinson's Disease, Beijing, China. [email protected].
  • 9. Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China. [email protected].
PMID: 41654526 DOI: 10.1038/s41531-026-01281-3
Abstract

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.

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