Parkinson's‐Linked LRRK2 and GBA1 Mutations Modulate the Peripheral Immune Response to Pseudomonas aeruginosa

Abstract Background Peripheral disease mechanisms such as immune dysregulation may contribute to Parkinson's disease ( PD ). To investigate interactions between common PD mutations and immune responses to environmental pathogens, we studied responses to Pseudomonas aeruginosa ( P. aeruginosa ) in peripheral blood mononuclear cells ( PBMCs ) from PD patients with leucine‐rich repeat kinase 2 ( LRRK2 ) mutations, GBA1 mutations, and idiopathic disease ( iPD ) relative to neurologically healthy controls ( NHC ). Objectives The goal was to test the hypothesis that LRRK2 and GBA modify the human peripheral immune response to bacteria, specifically P. aeruginosa , based on prior animal studies involving Lrrk2 mutations and microbial pathogens. Methods PBMCs from LRRK2 ‐ PD , GBA ‐ PD , and iPD patients plus age‐ and sex‐matched controls were treated ex vivo with live P. aeruginosa and pharmacological agents that block LRRK2 kinase activity ( MLi ‐2) or enhance glucocerebrosidase ( GCase ) activation ( NCGC00188758 ) to measure enzymatic activities and cytokine release. Results GBA ‐ PD PBMCs exhibited increased P. aeruginosa ‐dependent secretion of specific inflammatory cytokines including interleukin ‐1β. Antigen presentation was increased in LRRK2 ‐ PD nonclassical monocytes treated with the GCase activator. Levels of pRab10 , a proxy for LRRK2 kinase activity, were increased in GBA ‐ PD classical monocytes relative to NHC and iPD . GCase activator treatment increased pRab10 expression in LRRK2 ‐ PD intermediate monocytes. GBA ‐ PD and individual treatments with MLi ‐2 or GCase activator were associated with reduced P. aeruginosa ‐dependent LRRK2 protein levels in PBMC subsets. Conclusions This work demonstrates that PD ‐linked mutations in LRRK2 and GBA1 converge on peripheral blood immune cell dysregulation, as evinced by the ability of LRRK2 inhibitors and GCase activators to modulate the ex vivo immune response to bacterial exposure. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.