Loss of Leucine-Rich Repeat Kinase 2 (LRRK2) in Rats Leads to Progressive Abnormal Phenotypes in Peripheral Organs

Abstract

The objective of this study was to evaluate the pathology time course of the LRRK2 knockout rat model of Parkinson’s disease at 1-, 2-, 4-, 8-, 12-, and 16-months of age. The evaluation consisted of histopathology and ultrastructure examination of selected organs, including the kidneys, lungs, spleen, heart, and liver, as well as hematology, serum, and urine analysis. The LRRK2 knockout rat, starting at 2-months of age, displayed abnormal kidney staining patterns and/or morphologic changes that were associated with higher serum phosphorous, creatinine, cholesterol, and sorbitol dehydrogenase, and lower serum sodium and chloride compared to the LRRK2 wild-type rat. Urinalysis indicated pronounced changes in LRRK2 knockout rats in urine specific gravity, total volume, urine potassium, creatinine, sodium, and chloride that started as early as 1- to 2-months of age. Electron microscopy of 16-month old LRRK2 knockout rats displayed an abnormal kidney, lung, and liver phenotype. In contrast, there were equivocal or no differences in the heart and spleen of LRRK2 wild-type and knockout rats. These findings partially replicate data from a recent study in 4-month old LRRK2 knockout rats [1] and expand the analysis to demonstrate that the renal and possibly lung and liver abnormalities progress with age. The characterization of LRRK2 knockout rats may prove to be extremely valuable in understanding potential safety liabilities of LRRK2 kinase inhibitor therapeutics for treating Parkinson’s disease.

MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition

“…7,C and E). Unlike observations of kidney darkening in LRRK2 KO mice (Herzig et al, 2011;Baptista et al, 2013;Tong et al, 2012), MitoPark mice receiving rodent diet containing MLi-2 at 30 mg/kg per day for 15 weeks did not exhibit kidney darkening upon gross examination nor accumulation of pigment in renal cortical tubules on tissue section. MLi-2 treatment at 30 mg/kg per day for 15 weeks was associated with very slight enlargement of randomly scattered alveolar epithelial cells that had features consistent with type II pneumocytes.…”

Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration

“…Because of this report, but also data generated from LRRK2 KO rats, we generated a cohort of rats for the purpose of assessment of all pathologies previously attributed to the loss of LRRK2 expression or activity. However, PF-06447475 treatment for a 4-week period of time did not result in any of the expected abnormalities observed in LRRK2 KO rats or non-human primates treated with LRRK2 kinase inhibitors (17,18). In addition, PF-06447475 had mild or no effects on reducing total LRRK2 protein in brain and kidney homogenates.…”

“…4-week) LRRK2 kinase inhibition (17). Additionally, LRRK2 knockout rats and mice show pathologies in the lung and kidney that include LAMP2-postive organelle accumulation in type II pneumocytes in lung and renal tubule cells in the kidney (18,19). For these reasons, the therapeutic potential of LRRK2 kinase inhibitors needs additional clarification in animal models.…”

Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts

“…However, the value of this therapeutic approach has been challenged by the observation that treatment with LRRK2 kinase inhibitors results in significant lung toxicity in primates (16). In addition, LRRK2 knockout rodent models display severe kidney phenotypes (17,18). These results suggest that effective therapeutic intervention may require more subtle allosteric modulation of LRRK2 kinase activity, and highlight the critical importance of understanding the regulation and function of this enzyme.…”