(R1441C) LRRK2 induces the degeneration of SN dopaminergic neurons and alters the expression of genes regulating neuronal survival in a transgenic mouse model
(R1441C) LRRK2 induces the degeneration of SN dopaminergic neurons and alters the expression of genes regulating neuronal survival in a transgenic mouse model
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DOI：
10.1016/j.expneurol.2015.09.001
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发表时间：
2016-01
影响因子：
5.3
通讯作者：
Y. Weng;Chu-Yu Chen;Kun-Jun Lin;Ying-Ling Chen;T. Yeh;I. Hsiao;Ing-jou Chen;C. Lu;Hung-Li Wang
中科院分区：
文献类型：
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作者：
Y. Weng;Chu-Yu Chen;Kun-Jun Lin;Ying-Ling Chen;T. Yeh;I. Hsiao;Ing-jou Chen;C. Lu;Hung-Li Wang
富亮氨酸重复激酶2 （LRRK2）突变是家族性和散发性帕金森病（PD）病例最常见的遗传原因。PD患者中有LRRK2基因突变的报道。R1441是第二常见的LRRK2突变位点。我们培育了（R1441C） LRRK2转基因小鼠，这些小鼠在16个月大时表现出运动缺陷。与野生型小鼠相比，16月龄（R1441C） LRRK2小鼠黑质（SN）多巴胺能神经元数量显著减少。为了阐明（R1441C） LRRK2诱导SN多巴胺能神经元死亡的分子致病途径，我们通过微阵列分析可视化了（R1441C） LRRK2小鼠SN中mRNA表达的改变。在（R1441C） LRRK2转基因小鼠SN中，3个促进细胞死亡的基因mRNA表达上调，7个促进神经发生/神经保护的基因mRNA表达显著下调。我们的研究结果表明，这些参与调节神经元存活的基因表达的改变可能有助于（R1441C） lrrk2诱导PD的发病机制。
Mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Several mutations in LRRK2 gene were reported in PD patients. R1441 is the second most frequent site of LRRK2 mutation. We generated (R1441C) LRRK2 transgenic mice that displayed motor deficits at the age of 16 months. Compared with wild-type mice, 16-month-old (R1441C) LRRK2 mice exhibited a significant reduction in the number of substantia nigra (SN) dopaminergic neurons. To elucidate molecular pathogenic pathways involved in (R1441C) LRRK2-induced death of SN dopaminergic neurons, we performed microarray analysis to visualize altered mRNA expressions in the SN of (R1441C) LRRK2 mouse. In the SN of (R1441C) LRRK2 transgenic mouse, the mRNA expression of three genes that promote cell death was upregulated, while the mRNA expression of seven genes that contribute to neurogenesis/neuroprotection was significantly downregulated. Our results suggest that altered expression of these genes involved in regulating neuronal survival may contribute to the pathogenesis of (R1441C) LRRK2-induced PD.