G2019S-LRRK2 mutation enhances MPTP-linked Parkinsonism in mice
G2019S-LRRK2 mutation enhances MPTP-linked Parkinsonism in mice
复制标题
DOI：
10.1093/hmg/ddz271
复制
发表时间：
2020-02-15
影响因子：
3.5
通讯作者：
Ross, Christopher A.
中科院分区：
文献类型：
--
作者：
Arbez, Nicolas;He, XiaoFei;Ross, Christopher A.
帕金森病（PD）是一种常见的神经退行性疾病，其病因复杂，既有遗传因素，也有环境因素或外源性因素。目前的LRRK 2 PD动物模型仅部分再现了具有非常轻微的多巴胺能神经元变性的疾病的特征。我们开发了一种新的PD模型，将亚毒性MPTP损伤与G2019 S-LRRK 2突变相结合。我们新产生的小鼠，在大脑中过表达突变G2019 S-LRRK 2蛋白，显示出轻度的、年龄依赖性的进行性运动障碍，但寿命没有减少。与过表达野生型WT-LRRK 2或非转基因（nTg）神经元的神经元相比，G2019 S-LRRK 2小鼠的皮质神经元对应激损伤的脆弱性增加。LRRK 2转基因小鼠暴露于亚毒性剂量的MPTP导致严重的运动障碍，多巴胺神经元的选择性丧失和星形胶质细胞活化增加，而MPTP暴露的nTg小鼠没有表现出缺陷。有趣的是，过表达WT-LRRK 2的小鼠显示出比突变G2019 S-LRRK 2小鼠更轻微的显著损伤。左旋多巴治疗可部分改善运动障碍，但不能保护多巴胺神经元的丢失。相反，在这种相互作用模型中，用LRRK 2激酶抑制剂治疗显著减少多巴胺能神经元变性。我们的研究为进一步研究PD的发病机制和治疗干预提供了一种新的LRRK 2基因-MPTP相互作用的PD小鼠模型。
Parkinson's disease (PD) is a common neurodegenerative disease with a heterogeneous etiology that involves genetic and environmental factors or exogenous. Current LRRK2 PD animal models only partly reproduce the characteristics of the disease with very subtle dopaminergic neuron degeneration. We developed a new model of PD that combines a sub-toxic MPTP insult to the G2019S-LRRK2 mutation. Our newly generated mice, overexpressing mutant G2019S-LRRK2 protein in the brain, displayed a mild, age-dependent progressive motor impairment, but no reduction of lifespan. Cortical neurons from G2019S-LRRK2 mice showed an increased vulnerability to stress insults, compared with neurons overexpressing wild-type WT-LRRK2, or non-transgenic (nTg) neurons. The exposure of LRRK2 transgenic mice to a sub-toxic dose of MPTP resulted in severe motor impairment, selective loss of dopamine neurons and increased astrocyte activation, whereas nTg mice with MPTP exposure showed no deficits. Interestingly, mice overexpressing WT-LRRK2 showed a significant impairment that was milder than for the mutant G2019S-LRRK2 mice. L-DOPA treatments could partially improve the movement impairments but did not protect the dopamine neuron loss. In contrast, treatments with an LRRK2 kinase inhibitor significantly reduced the dopaminergic neuron degeneration in this interaction model. Our studies provide a novel LRRK2 gene-MPTP interaction PD mouse model, and a useful tool for future studies of PD pathogenesis and therapeutic intervention.