Mouse models for LRRK2 Parkinson's disease.
Mouse models for LRRK2 Parkinson's disease.
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DOI：
10.1016/s1353-8020(11)70058-x
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发表时间：
2012
影响因子：
4.1
通讯作者：
Qing Xu;Sushila A. Shenoy;Chenjian Li
中科院分区：
文献类型：
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作者：
Qing Xu;Sushila A. Shenoy;Chenjian Li
帕金森病（Parkinson's disease，PD）是第二常见的神经退行性疾病。富含亮氨酸重复序列激酶2（Leucine-rich-repeat-kinase 2，LRRK 2）是PARK 8型PD的致病基因，具有常染色体显性遗传，是家族性和散发性PD最常见的遗传病因。动物模型是试图了解LRRK 2介导的发病机制的关键工具。我们已经产生了人类细菌人工染色体（BAC）介导的转基因小鼠模型表达突变LRRK 2，强大的概括行为，神经化学和病理特征的PD。这些小鼠的运动活动出现年龄依赖性下降，这种下降是进行性的，并对左旋多巴治疗有反应。病理学上，最突出的表型是黑质纹状体多巴胺能神经元的早期轴突病，伴有过度磷酸化的tau蛋白。小鼠在急性脑切片和自由活动的动物中也表现出一致的多巴胺传递缺陷。在这里，我们将讨论来自几个实验室的LRRK 2小鼠模型，它们的共性和差异，并提供从这些研究中得出的科学见解。
Parkinson's disease (PD) is the second most common neurodegenerative disease. Mutations in Leucine-rich-repeat-kinase 2 (LRRK2), the causative gene for PARK8 type PD with autosomal dominant inheritance, are the most prevalent genetic causes of both familial and sporadic PD. Animal models are critical tools in the attempt to understand the mechanisms of LRRK2-mediated pathogenesis. We have generated human Bacterial Artificial Chromosome (BAC) mediated transgenic mouse models expressing mutant LRRK2 that robustly recapitulate the behavioral, neurochemical and pathological features of PD. These mice develop an age-dependent decrease in motor activity that is progressive and responds to treatment with levodopa. Pathologically, the most salient phenotype is early axonopathy of nigrostriatal dopaminergic neurons, accompanied by hyperphosphorylated tau. The mice also exhibit a consistent dopamine transmission deficit in both acute brain slices and live freely moving animals. Here we will discuss LRRK2 mouse models from several laboratories, their commonalities and differences, and offer scientific insights drawn from these studies.