LRRK2-G2019S Synergizes With Ageing and Low-Grade Inflammation to Promote Gut and Peripheral Immune Cell Activation That Precede Nigrostriatal Degeneration

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson's disease (PD). The incomplete penetrance of LRRK2 mutations suggest that additional hits are required for disease onset. We hypothesized that chronic low-grade inflammation interacts with LRRK2 G2019S, the most frequent PD-associated mutation, to activate peripheral and central immune reactions and drive age-dependent neurodegeneration. We exposed wild-type and LRRK2 G2019S mice to a low chronic dose of lipopolysaccharide and performed a longitudinal analysis of central and peripheral immune reactions and neurodegeneration. Low-dose inflammation triggered nigrostriatal degeneration, peripheral monocyte infiltration, and astro-/microgliosis. LRRK2 G2019S mice showed an early dysregulation of peripheral cytokines as well as increased CD4+ T-cell infiltration and α-synuclein aggregation in the colon. Peripheral immune activation and colonic α-synuclein aggregation preceded brain inflammation and degeneration. Our study suggests an early role of the peripheral immune system and the gut in LRRK2 PD and provides a novel model to study early therapeutic immune targets and biomarkers.