RT Journal Article
SR Electronic
T1 LRRK2-G2019S Synergizes with Ageing and Low-Grade Inflammation to Promote Gut and Peripheral Immune Cell Activation that Precede Nigrostriatal Degeneration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.09.01.505977
DO 10.1101/2022.09.01.505977
A1 Giachino, Carmela
A1 Tirolo, Cataldo
A1 Caniglia, Salvatore
A1 Serapide, Maria F.
A1 L’Episcopo, Francesca
A1 Bertoli, Federico
A1 Giuliano, Claudio
A1 Mearelli, Marika
A1 Jakobi, Meike
A1 Schneiderhan-Marra, Nicole
A1 Deleidi, Michela
A1 Marchetti, Bianca
YR 2022
UL http://biorxiv.org/content/early/2022/09/03/2022.09.01.505977.abstract
AB Background 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.Methods and Results We exposed wild-type and LRRK2 G2019S mice to a low chronic dose of lipopolysaccharide, and we performed a longitudinal analysis of central and peripheral immune reactions and neurodegeneration. Low-dose inflammation triggered nigrostriatal degeneration, macrophage/monocyte brain infiltration, and astro-/microgliosis. LRRK2 G2019S mice showed an early dysregulation of peripheral cytokines, increased CD4+ T-cell infiltration and α-synuclein aggregation in the colon. Interestingly, peripheral immune activation and colonic α-synuclein aggregation precede astro-/microgliosis and neurodegeneration.Conclusions 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.Competing Interest StatementThe authors have declared no competing interest.