LRRK2 G2019S variant triggers transcriptional changes in Parkinson's disease human myeloid cells under pro-inflammatory environment

The G2019S mutation in the LRRk2 gene is a major Parkinson's disease risk factor. We studied its effect on microglial activity and found that it remains inactive under normal conditions but strongly affects gene regulation when exposed to inflammation such as LPS and IFNg. The mutation increases lipid metabolism and phagolysosomal genes in microglia, enhancing their ability to clear myelin debris. It also disrupts cell cycle genes, decreasing proliferation and E2F4 regular.These findings reveal G2019S's significant impact on myeloid cell gene activity during inflammation, highlighting lipid imbalance as a key factor in functional disruptions. Overall design: All experiments were performed with monocytes derived from cryopreserved PBMCs to avoid any technical variability, and were performed in 2 independent experimental batches Genotypes: LRRk2 (Wt), LRRK2 G2019S mutation (Het), LRRK2 G2019S mutation (Hom) Treatments: Basal, IFNg, LPS