Pei Jessica, Oliveira Nathalia L, Recinto Sherilyn J, Kazanova Alexandra, Queiroz-Junior Celso M, Li Ziyi, Couto Katalina, Westfall Susan, Fahmy Ahmed M, Tiefensee-Ribeiro Camila, King Irah L, Milnerwood Austen J, Desjardins Michel, Thanabalasuriar Ajitha, Stratton Jo Anne, Gruenheid Samantha
Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
NPJ Parkinsons Dis. 2025 Aug 29;11(1):267. doi: 10.1038/s41531-025-01077-x.
Parkinson's Disease (PD) is a neurodegenerative disorder often preceded by gastrointestinal dysfunction. Mutations in leucine-rich repeat kinase 2 (LRRK2) are known risk factors for both PD and inflammatory bowel disease (IBD), suggesting a link between PD and the gastrointestinal tract. Using single-cell RNA-sequencing and spectral flow cytometry, we demonstrated that the Lrrk2 Gly2019Ser (G2019S) mutation is associated with an increased neutrophil presence in the colonic lamina propria during Citrobacter rodentium infection. This concurred with a Th17 skewing, upregulated Il17a, and greater colonic pathology during infection. In vitro experiments showed enhanced kinase-dependent neutrophil chemotaxis and neutrophil extracellular trap (NET) formation in Lrrk2 G2019S mice compared to wild-type counterparts. Our results add to the understanding of LRRK2-driven immune cell dysregulation and its contribution to PD, offering insights into potential biomarkers for early diagnosis and intervention in PD.
帕金森病（PD）是一种神经退行性疾病，通常在出现胃肠道功能障碍之前就已发生。富含亮氨酸重复激酶2（LRRK2）的突变是PD和炎症性肠病（IBD）的已知风险因素，这表明PD与胃肠道之间存在联系。通过单细胞RNA测序和光谱流式细胞术，我们证明Lrrk2 Gly2019Ser（G2019S）突变与鼠柠檬酸杆菌感染期间结肠固有层中嗜中性粒细胞数量增加有关。这与感染期间Th17偏向、Il17a上调以及更严重的结肠病理状况一致。体外实验表明，与野生型小鼠相比，Lrrk2 G2019S小鼠的激酶依赖性嗜中性粒细胞趋化性增强，嗜中性粒细胞胞外陷阱（NET）形成增加。我们的研究结果有助于加深对LRRK2驱动的免疫细胞失调及其对PD的影响的理解，为PD的早期诊断和干预提供潜在生物标志物的见解。
