Terina N. Martinez¹, Marco A.S. Baptista¹, Melanie A. Greeley², Mark T. Herberth², Daniel Kovarik¹, Adria Martig¹, Kuldip D. Dave¹,Mark A. Frasier¹, Brian Fiske¹, and Todd Sherer¹

Affiliations: The Michael J. Fox Foundation for Parkinson's Research¹, WIL Research²

Several mutations in the gene leucine-rich repeat kinase 2 (LRRK2) are associated with autosomal-dominant late onset Parkinson's disease (PD). The common G2019S mutation in the kinase domain increases LRRK2 kinase activity and may explain LRRK2-related PD pathology. Thus, inhibition of LRRK2 kinase activity is an attractive target for developing novel therapeutic approaches for PD patients. As part of a broad effort to determine the impact of loss of LRRK2 function, which may be concomitant to pharmacological inhibition of LRRK2 kinase activity, we undertook a rigorous study of histological and clinical pathology readouts in LRRK2-related mouse and rat models. We previously reported progressive kidney pathology (cytoplasmic vacuolation, hyaline droplets, and pigment accumulation) and mild lung pathology (observed only with advanced age and by electron microscopy analysis) associated with loss of LRRK2 in Long Evans rats at several ages (Baptista, M.A. et al., PLOS One, 2013). Here we summarize recent pathology findings in LRRK2^-/- and LRRK2^+/+ C57Bl/6 mice at several ages, LRRK2 gene dosage effects in LRRK2^-/-, LRRK2^+/- and LRRK2^+/+ rats, and potential LRRK1 genetic interaction in LRRK1/2 double knockout versus wild type rats. The progressive kidney pathology findings in LRRK2^-/- mice generally recapitulated previous observations in LRRK2^-/- rat models albeit with some species differences, including an apparent earlier onset in mice compared to rats. In addition, lung pathology (cytoplasmic vacuolation in Type II pneumocytes) was more severe in LRRK2^-/- mice than in LRRK2^-/- rats and observable using light microscopy. In the rat studies, we observed evidence of a LRRK2 gene-dosage effect for kidney pathology and apparent exacerbation of LRRK2-related kidney pathology with loss of LRRK1. However, studies to examine potential LRRK2 gene dosage effects or LRRK1 interactions were not conducted in mice. These results may inform follow-up pathology and toxicology studies aimed at therapeutic strategies to modulate LRRK2 levels or kinase activity.