Selective expression of Parkinson's disease-related Leucine-rich repeat kinase 2 G2019S missense mutation in midbrain dopaminergic neurons impairs dopamine release and dopaminergic gene expression
Selective expression of Parkinson's disease-related Leucine-rich repeat kinase 2 G2019S missense mutation in midbrain dopaminergic neurons impairs dopamine release and dopaminergic gene expression
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DOI：
10.1093/hmg/ddv249
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发表时间：
2015-09-15
影响因子：
3.5
通讯作者：
Cai, Huaibin
中科院分区：
文献类型：
--
作者：
Liu, Guoxiang;Sgobio, Carmelo;Cai, Huaibin
中脑黑质致密部(SNPC)多巴胺能(DA)神经元的优先功能障碍/变性是帕金森病(PD)的主要运动症状之一。尽管富含亮氨酸的重复蛋白激酶2(LRRK2)G2019S错义突变(LRRK2 G2019S)是与帕金森病相关的最常见的遗传因素，但LRRK2 G2019S对SNPC DA神经元的功能和存活的影响尚不清楚。利用双基因表达系统，我们获得了在中脑DA神经元中选择性表达野生型人类LRRK2(WT小鼠)或LRRK2 G2019S突变(G2019S小鼠)的转基因小鼠。在这里，我们表明LRRK2 G2019S的过表达没有引起明显的运动异常或实质性的SNPC DA神经元丢失。然而，LRRK2 G2019S突变损害了老年小鼠的多巴胺稳态和释放。多巴胺含量/释放的减少与DA轴突终末的变性和DA神经元丰富的基因酪氨酸羟基酶(TH)、囊泡单胺转运体2、多巴胺转运体和乙醛脱氢酶1的表达减少相一致。这些因子负责多巴胺的合成、运输和降解，它们的表达受转录因子类同源域3(PITX3)的调节。老年G2019S小鼠SNPC DA神经元中的Pitx3mRNA和蛋白水平也同样降低。综上所述，这些发现表明，依赖PITX3的转录调控可能是LRRK2 G2019S作用于SNPC DA神经元的众多潜在机制之一，导致其下游对多巴胺稳态和释放至关重要的靶基因下调。
Preferential dysfunction/degeneration of midbrain substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons contributes to the main movement symptoms manifested in Parkinson's disease (PD). Although the Leucine-rich repeat kinase 2 (LRRK2) G2019S missense mutation (LRRK2 G2019S) is the most common causative genetic factor linked to PD, the effects of LRRK2 G2019S on the function and survival of SNpc DA neurons are poorly understood. Using a binary gene expression system, we generated transgenic mice expressing either wild-type human LRRK2 (WT mice) or the LRRK2 G2019S mutation (G2019S mice) selectively in the midbrain DA neurons. Here we show that overexpression of LRRK2 G2019S did not induce overt motor abnormalities or substantial SNpc DA neuron loss. However, the LRRK2 G2019S mutation impaired dopamine homeostasis and release in aged mice. This reduction in dopamine content/ release coincided with the degeneration of DA axon terminals and decreased expression of DA neuron-enriched genes tyrosine hydroxylase (TH), vesicular monoamine transporter 2, dopamine transporter and aldehyde dehydrogenase 1. These factors are responsible for dopamine synthesis, transport and degradation, and their expression is regulated by transcription factor paired-like homeodomain 3 (PITX3). Levels of Pitx3 mRNA and protein were similarly decreased in the SNpc DA neurons of aged G2019S mice. Together, these findings suggest that PITX3-dependenttranscription regulation could be one of the many potential mechanisms by which LRRK2 G2019S acts in SNpc DA neurons, resulting in downregulation of its downstream target genes critical for dopamine homeostasis and release.