Parkinson's disease-associated LRRK2 G2019S enhances intestinal neutrophil extracellular trap formation through RAB10–myeloperoxidase signaling and promotes enteric α-synuclein accumulation

Research overview

The text below is the source article’s original abstract under a verified reuse license. cc by

Abstract Background Gastrointestinal inflammation has been implicated in Parkinson’s disease (PD), and inflammatory bowel disease is associated with increased PD risk. Leucine-rich repeat kinase 2 (LRRK2) is a major PD-associated gene, an inflammatory bowel disease susceptibility locus, and is highly expressed in neutrophils. How pathogenic LRRK2 alters neutrophil effector function in the inflamed gut and whether this contributes to a PD-relevant enteric phenotype remain unclear. Methods LRRK2 G2019S transgenic mice and non-transgenic littermates were subjected to acute and repeated dextran sulfate sodium-induced colitis. Colonic neutrophil extracellular trap (NET) formation, lamina propria immune populations, and enteric α-synuclein were assessed by immunofluorescence, flow cytometry, and immunoblotting, respectively. NETs were targeted by DNase I treatment and PAD4 deficiency, and microbiota dependence was examined in germ-free mice. Mechanistic studies used primary bone marrow neutrophils and RAB10-mutant neutrophil-like HL-60 cells with LRRK2 kinase inhibition, pathway-selective pharmacology, immunoblotting, and three-dimensional confocal analysis. Results LRRK2 G2019S mice developed more severe recurrent colitis with increased colonic NET formation but no increase in neutrophil infiltration. Elevated NET formation was already evident during acute colitis before genotype-dependent differences in overall disease severity emerged. DNase I treatment and PAD4 deficiency each reduced intestinal pathology and lowered colonic α-synuclein, whereas germ-free conditions abolished colonic NETs and the genotype-dependent α-synuclein increase. Ex vivo, LRRK2 G2019S neutrophils released more NETs in a kinase-dependent manner and showed increased RAB10 Thr73 phosphorylation; phosphomimetic RAB10 was sufficient to enhance NET release. This effect required myeloperoxidase (MPO) and hypochlorous acid (HOCl), whereas HOCl scavenging did not reduce RAB10 phosphorylation, functionally placing RAB10 phosphorylation upstream of the MPO–HOCl axis. Phosphorylated RAB10 and MPO showed increased co-occurrence with DNA⁺ regions in a kinase-dependent manner. Conclusions These findings identify a neutrophil-centered LRRK2–RAB10–myeloperoxidase pathway that promotes excessive NET formation during intestinal inflammation and links PD-associated LRRK2 hyperactivity to intestinal pathology and enteric α-synuclein accumulation. Peripheral neutrophil effector programming may therefore represent an inflammatory mechanism at the gut–brain interface in PD.

Related topics