Center for Human Genetics, K. U. Leuven, Belgium.
Neurobiol Dis. 2012 Dec;48(3):582-93. doi: 10.1016/j.nbd.2012.07.017. Epub 2012 Jul 29.
In spite of a clear genetic link between Parkinson's disease (PD) and mutations in LRRK2, cellular localization and physiological function of LRRK2 remain debated. Here we demonstrate the immunohistochemical localization of LRRK2 in adult mouse and early postnatal mouse brain development. Antibody specificity is verified by absence of specific staining in LRRK2 knockout mouse brain. Although LRRK2 is expressed in various mouse brain regions (i.e. cortex, thalamus, hippocampus, cerebellum), strongest expression is detected in striatum, whereas LRRK2 protein expression in substantia nigra pars compacta in contrast is low. LRRK2 is highly expressed in striatal medium spiny neurons (MSN) and few cholinergic interneurons. LRRK2 expression is undetectable in other interneurons, oligodendrocytes or astrocytes of the striatum. Interestingly, LRRK2 expression is associated with striosome specific markers (i.e. MOR1, RASGRP1). Analysis of LRRK2 expression during early postnatal development and in LRRK2 knockout mice, demonstrates that LRRK2 is not required for generation or maintenance of the striosome compartment. Comparing LRRK2-WT, LRRK2-R1441G transgenic and non-transgenic mice, changes of LRRK2 expression in striosome/matrix compartments can be detected. The findings rule out a specific requirement of LRRK2 in striosome genesis but suggest a functional role for LRRK2 in striosomes.
尽管帕金森病（PD）与 LRRK2 突变之间存在明显的遗传联系，但 LRRK2 的细胞定位和生理功能仍存在争议。在这里，我们展示了 LRRK2 在成年小鼠和早期产后小鼠大脑发育中的免疫组织化学定位。通过在 LRRK2 敲除小鼠大脑中不存在特异性染色来验证抗体特异性。尽管 LRRK2 在各种小鼠脑区（即皮层、丘脑、海马、小脑）中表达，但在纹状体中表达最强，而 LRRK2 蛋白在黑质致密部的表达则较低。LRRK2 在纹状体中型棘突神经元（MSN）和少数胆碱能中间神经元中高度表达。LRRK2 在其他中间神经元、少突胶质细胞或纹状体星形胶质细胞中无法检测到表达。有趣的是，LRRK2 的表达与纹状体特定标志物（即 MOR1、RASGRP1）相关联。在早期产后发育过程中和 LRRK2 敲除小鼠中分析 LRRK2 的表达，表明 LRRK2 对于纹状体隔室的产生或维持不是必需的。比较 LRRK2-WT、LRRK2-R1441G 转基因和非转基因小鼠，可检测到纹状体/基质隔室中 LRRK2 表达的变化。这些发现排除了 LRRK2 在纹状体发生中的特定要求，但表明 LRRK2 在纹状体中具有功能作用。
