Lrrk2 G2019S mutation incites increased cell-intrinsic neutrophil effector functions and intestinal inflammation in a model of infectious colitis
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.
Authors
- Austen J. Milnerwood (ORCID: https://orcid.org/0000-0002-0056-1778)
- Samantha Gruenheid (ORCID: https://orcid.org/0000-0002-0908-6715)
- Alexandra Kazanova (ORCID: https://orcid.org/0000-0003-4850-9845)
- Ahmed M. Fahmy (ORCID: https://orcid.org/0000-0003-0444-383X)
- Celso Martins Queiroz‐Junior (ORCID: https://orcid.org/0000-0002-7884-7709)
- Camila Tiefensee Ribeiro (ORCID: https://orcid.org/0000-0003-0876-119X)
- Sherilyn Junelle Recinto (ORCID: https://orcid.org/0000-0001-9632-1201)
- Ajitha Thanabalasuriar (ORCID: https://orcid.org/0000-0001-6281-3013)
- Susan Westfall (ORCID: https://orcid.org/0000-0003-4974-0379)
- Jo Anne Stratton (ORCID: https://orcid.org/0000-0002-1205-1353)
- Ziyi Li (ORCID: https://orcid.org/0009-0008-8071-0737)
- Irah L. King (ORCID: https://orcid.org/0000-0001-6990-7231)
- Michel Desjardins (ORCID: https://orcid.org/0000-0002-5684-5980)
- Nathalia Luisa Oliveira (ORCID: https://orcid.org/0000-0002-5823-2184)
- Katalina Couto
Institutions
- Universidade Federal de Minas Gerais (BR)
- Montreal Neurological Institute and Hospital (CA)
- Research Network (United States) (US)
- McGill University (CA)
- Université de Montréal (CA)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1038/s41531-025-01077-x
- Primary Topic
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Michael J. Fox Foundation for Parkinson's Research
- McGill University
- Aligning Science Across Parkinson’s
- Canadian Institutes of Health Research