Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs.
Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs.
复制标题
大鼠富含亮氨酸重复激酶 2 (LRRK2) 的缺失会导致外周器官逐渐出现异常表型。
DOI：
10.1371/journal.pone.0080705
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Fiske BK
中科院分区：
文献类型：
--
作者：
Baptista MA;Dave KD;Frasier MA;Sherer TB;Greeley M;Beck MJ;Varsho JS;Parker GA;Moore C;Churchill MJ;Meshul CK;Fiske BK
本研究的目的是评估帕金森病的LRRK 2敲除大鼠模型在1、2、4、8、12和16月龄时的病理学时程。评价包括选定器官的组织病理学和超微结构检查，包括肾、肺、脾、心脏和肝脏，以及血液学、血清和尿液分析。LRRK 2敲除大鼠，从2个月大开始，显示异常的肾脏染色模式和/或形态学变化，与较高的血清磷，肌酐，胆固醇，山梨醇脱氢酶，和较低的血清钠和氯相比，LRRK 2野生型大鼠。尿分析表明，早在1至2个月大时，LRRK 2敲除大鼠的尿比重、总体积、尿钾、肌酐、钠和氯化物就发生了显著变化。16个月大的LRRK 2基因敲除大鼠的电子显微镜检查显示肾脏、肺和肝脏表型异常，而野生型和LRRK 2基因敲除大鼠的心脏和脾脏则无明显差异。这些发现部分复制了最近在4个月大的LRRK 2基因敲除大鼠中进行的研究的数据，并扩展了分析，以证明肾脏以及可能的肺和肝脏异常随年龄而进展。LRRK 2基因敲除大鼠的表征可能被证明在理解LRRK 2激酶抑制剂治疗帕金森病的潜在安全性方面是非常有价值的。
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 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.
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影响因子：
3.7
作者：
Ness D;Ren Z;Gardai S;Sharpnack D;Johnson VJ;Brennan RJ;Brigham EF;Olaharski AJ
通讯作者：
Olaharski AJ
影响因子：
3.5
作者：
Nussbaum, RL;Polymeropoulos, MH
通讯作者：
Polymeropoulos, MH
DOI：
10.1073/pnas.0507360102
发表时间：
2005-11-15
影响因子：
11.1
作者：
West, AB;Moore, DJ;Dawson, TM
通讯作者：
Dawson, TM
影响因子：
1.5
作者：
Zhang J;Goering PL;Espandiari P;Shaw M;Bonventre JV;Vaidya VS;Brown RP;Keenan J;Kilty CG;Sadrieh N;Hanig JP
通讯作者：
Hanig JP
DOI：
10.1073/pnas.1004676107
发表时间：
2010-05-25
影响因子：
11.1
作者：
Tong, Youren;Yamaguchi, Hiroo;Shen, Jie
通讯作者：
Shen, Jie