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

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.

本研究旨在评估LRRK2基因敲除（LRRK2 knockout）帕金森病（Parkinson’s disease）大鼠模型在1、2、4、8、12及16月龄时的病理病程变化。本次评估涵盖肾脏、肺脏、脾脏、心脏、肝脏等选定器官的组织病理学与超微结构检查，同时开展血液学、血清学及尿液分析检测。与LRRK2野生型（wild-type）大鼠相比，2月龄起的LRRK2基因敲除大鼠便呈现肾脏染色模式异常及/或形态学改变，同时伴随血清磷、肌酐、胆固醇与山梨醇脱氢酶水平升高，血清钠与氯水平降低。尿液分析结果显示，LRRK2基因敲除大鼠早在1至2月龄时，便出现尿比重、总尿量、尿钾、肌酐、钠及氯水平的显著变化。对16月龄LRRK2基因敲除大鼠的电子显微镜（electron microscopy）检查显示，其肾脏、肺脏及肝脏存在异常表型。与之相反，LRRK2野生型与基因敲除大鼠的心脏与脾脏仅存在不明确差异或无明显差异。本研究结果部分复现了近期一项针对4月龄LRRK2基因敲除大鼠的研究数据[1]，并拓展了分析范围，证实肾脏及可能累及的肺脏、肝脏异常会随年龄进展而加重。对LRRK2基因敲除大鼠的特征解析，或将为理解用于治疗帕金森病的LRRK2激酶抑制剂（kinase inhibitor）类治疗药物的潜在安全性隐患提供极具价值的参考依据。