LRRK2 G2019S variant is associated with transcriptional changes in Parkinson’s disease human myeloid cells under proinflammatory environment

@article{navarro2026lrrk2,
  title = {{LRRK2 G2019S variant is associated with transcriptional changes in Parkinson’s disease human myeloid cells under proinflammatory environment}},
  author = {Elisa Navarro and Anastasia G. Efthymiou and Daniele Mattei and Madison Parks and Giulietta Maria Riboldi and Ricardo A. Vialle and Evan Udine and Benjamin Z. Muller and Jack Humphrey and Amanda Allan and Charalambos Argyrou and Katia de Paiva Lopes and Alexandra Münch and Deborah Raymond and Rivka Sachdev and Vicki L. Shanker and Joan Miravite and Viktoriya Katsnelson and Katherine Leaver and Steven Frucht and Susan B. Bressman and Edoardo Marcora and Rachel Saunders-Pullman and Alison M. Goate and Towfique Raj},
  journal = {Journal of Neuroinflammation},
  year = {2026},
  month = aug,
  doi = {10.1186/s12974-026-03967-0},
  url = {https://doi.org/10.1186/s12974-026-03967-0},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - LRRK2 G2019S variant is associated with transcriptional changes in Parkinson’s disease human myeloid cells under proinflammatory environment
AU  - Elisa Navarro
AU  - Anastasia G. Efthymiou
AU  - Daniele Mattei
AU  - Madison Parks
AU  - Giulietta Maria Riboldi
AU  - Ricardo A. Vialle
AU  - Evan Udine
AU  - Benjamin Z. Muller
AU  - Jack Humphrey
AU  - Amanda Allan
AU  - Charalambos Argyrou
AU  - Katia de Paiva Lopes
AU  - Alexandra Münch
AU  - Deborah Raymond
AU  - Rivka Sachdev
AU  - Vicki L. Shanker
AU  - Joan Miravite
AU  - Viktoriya Katsnelson
AU  - Katherine Leaver
AU  - Steven Frucht
AU  - Susan B. Bressman
AU  - Edoardo Marcora
AU  - Rachel Saunders-Pullman
AU  - Alison M. Goate
AU  - Towfique Raj
PY  - 2026
DA  - 2026/08/08
JO  - Journal of Neuroinflammation
DO  - 10.1186/s12974-026-03967-0
UR  - https://doi.org/10.1186/s12974-026-03967-0
AB  - The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson’s disease (PD). LRRK2, although expressed in different cell types, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation in untreated culture conditions and following exposure to the proinflammatory factors IFNγ and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFNγ stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12974-026-03967-0.
SN  - 1742-2094
ER  -