Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents.
Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents.
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转基因和非转基因啮齿类动物皮层、纹状体和黑质中 LRRK2 表达的差异。
DOI：
10.1002/cne.23583
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Volpicelli-Daley,LauraA
中科院分区：
文献类型：
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作者：
West,AndrewB;Cowell,RitaM;Daher,JoãoPL;Moehle,MarkS;Hinkle,KellyM;Melrose,HeatherL;Standaert,DavidG;Volpicelli-Daley,LauraA
在相当大比例的晚发性帕金森病(PD)患者中发现了富含亮氨酸的重复蛋白激酶2(LRRK2)的突变。阐明LRRK2的神经解剖学定位将进一步阐明LRRK2的功能和帕金森病的分子基础。在这里，我们利用最近鉴定的单抗来评估LRRK2在啮齿动物大脑中与帕金森病相关的区域的表达。在小鼠和大鼠中，LRRK2在皮质和纹状体高表达，特别是在V层锥体神经元和纹状体中的中等刺神经元。总体而言，与小鼠相比，大鼠的LRRK2分布更加有限。小鼠，而不是大鼠，在黑质致密部表现出高水平的LRRK2表达。来自小鼠细菌人工染色体(BAC)的致病LRRK2-G2019S蛋白的表达结构与内源性LRRK2在小鼠脑中的分布非常相似。然而，来自人BAC结构的LRRK2-G2019S的表达导致LRRK2在大鼠的其他神经元亚型中表达，如纹状体胆碱能中间神经元和黑质致密部。LRRK2在人类BAC结构中的分布与LRRK2在人类和非人灵长类动物中的描述更加相似。对LRRK2中DNA调控元件的计算分析表明，LRRK2中有一个灵长类特有的启动子序列，这是低等哺乳动物中不存在的。这些非编码区可能参与指导神经元的表达模式。总之，这些研究将有助于了解LRRK2在大脑中的正常功能，并将有助于未来研究的模型选择。J.Comp.神经。2014年522：2465-2480。©2014 Wiley期刊，Inc.
Mutations inleucine‐rich repeat kinase 2(LRRK2) are found in a significant proportion of late‐onset Parkinson's disease (PD) patients. Elucidating the neuroanatomical localization of LRRK2 will further define LRRK2 function and the molecular basis of PD. Here, we utilize recently characterized monoclonal antibodies to evaluate LRRK2 expression in rodent brain regions relevant to PD. In both mice and rats, LRRK2 is highly expressed in the cortex and striatum, particularly in pyramidal neurons of layer V and in medium spiny neurons within striosomes. Overall, rats have a more restricted distribution of LRRK2 compared with mice. Mice, but not rats, show high levels of LRRK2 expression in the substantia nigra pars compacta. Expression of the pathogenic LRRK2‐G2019S protein from mouse bacterial artificial chromosome (BAC) constructs closely mimics endogenous LRRK2 distribution in the mouse brain. However, LRRK2‐G2019S expression derived from human BAC constructs causes LRRK2 to be expressed in additional neuron subtypes in the rat such as striatal cholinergic interneurons and the substantia nigra pars compacta. The distribution of LRRK2 from human BAC constructs more closely resembles descriptions of LRRK2 in humans and nonhuman primates. Computational analyses of DNA regulatory elements in LRRK2 show a primate‐specific promoter sequence that does not exist in lower mammalian species. These noncoding regions may be involved in directing neuronal expression patterns. Together, these studies will aid in understanding the normal function of LRRK2 in the brain and will assist in model selection for future studies. J. Comp. Neurol. 522:2465–2480, 2014. © 2014 Wiley Periodicals, Inc.