The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner

Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered. We demonstrate here that the R1441C mutation induces a hyper-responsive phenotype in macrophages from young female mice, characterized by increased effector functions, including stimulation-dependent antigen presentation, cytokine release, phagocytosis, and lysosomal function. This is followed by age-acquired immune cell exhaustion in a Lrrk2-kinase-dependent manner. Immune-exhausted macrophages exhibit suppressed antigen presentation and hypophagocytosis, which is also demonstrated in myeloid cells from R1441C and Y1699C-PD patients. Our novel findings that LRRK2 mutations confer immunological advantage at a young age but may predispose the carrier to age-acquired immune exhaustion have significant implications for LRRK2 biology and therapeutic development. Indeed, LRRK2 has become an appealing target in PD, but our findings suggest that more research is required to understand the cell-type specific consequences and optimal timing of LRRK2-targeting therapeutics. The primary objective of this research was to investigate the effects of the R1441C LRRK2 pathogenic variant on myeloid cell effector function in a sex- and age-dependent manner. We hypothesized that a biphasic, age-dependent effect of the R1441C pathogenic variant would be observed, affecting antigen presentation, cytokine release, phagocytosis and lysosomal function in macrophages. To explore our hypothesis, we used R1441C knock-in mice and B6 controls and assessed myeloid cell effector function both ex vivo and in vivo, in males and females at 2-3 months and 18-21 months. All studies were performed by investigators blinded to genotype and treatment groups at the University of Florida, USA. Power analyses based on the labs pilot and published data indicated that n = 12 per group for flow-cytometry and cytokine release assays, and n = 6 for imaging based immunophenotyping and immunoblotting would be needed to yield 80% power with a α set to 0.05. The study used human PBMCs received from collaborators at University Hospital Schleswig-Holstein, University of Luebeck, Germany and the University Hospital Eppendorf, Hamburg, Germany. Samples were received at the University of Florida and investigators were unblinded after completion of analysis. Deidentified data provided included sex, age at collection, age of diagnosis, clinical diagnosis and genetic status.