The potassium channel KCa3.1 represents a valid pharmacological target for microgliosis-induced neuronal impairment in a mouse model of Parkinson's disease
The potassium channel KCa3.1 represents a valid pharmacological target for microgliosis-induced neuronal impairment in a mouse model of Parkinson's disease
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钾通道 KCa3.1 是帕金森病小鼠模型中小胶质细胞增生引起的神经元损伤的有效药理学靶点
DOI：
10.1186/s12974-019-1682-2
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发表时间：
2019-12-26
影响因子：
9.3
通讯作者：
Yu, Zhihua
中科院分区：
文献类型：
--
作者：
Lu, Jia;Dou, Fangfang;Yu, Zhihua
背景：最近的研究描述了小胶质细胞在帕金森病（PD）中的关键作用，这些中枢神经系统驻留免疫细胞参与神经炎症微环境，导致黑质多巴胺能神经元丢失。了解PD小胶质瘤的表型转换，有助于确定减轻或延缓运动功能进行性衰退的分子机制。据报道，KCa3.1在神经退行性病理条件下调节小胶质细胞的“促炎”表型转换。方法：研究1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）治疗小鼠PD模型后，基因缺失或药物阻断对野生型或KCa3.1（-/-）小鼠KCa3.1活性的影响。采用旋转棒法评价mptp诱导的PD小鼠模型的运动能力。免疫染色检测神经胶质细胞活化和神经元损失。采用Fluo-4 AM测定1-甲基-4-苯基吡啶（MPP+）诱导的体外小胶质瘤细胞内Ca2+水平。结果：我们报道了用senicapoc基因缺失或药物阻断KCa3.1治疗mptp诱导的PD小鼠模型，改善了运动能力和酪氨酸羟化酶（TH）阳性神经元数量，减轻了黑质致密部（SNpc）的小胶质细胞增生和神经炎症。在小胶质细胞形成过程中，KCa3.1通过蛋白激酶B （AKT）信号通路参与储存性Ca2+进入诱导的Ca2+过载和内质网应激。基因缺失或阻断KCa3.1在体内和体外均可恢复AKT/哺乳动物雷帕霉素靶（mTOR）信号。综上所述，这些结果证明了KCa3.1在PD中驱动促炎性小胶质细胞表型中的关键作用。
Background: Recent studies described a critical role for microglia in Parkinson's disease (PD), where these central nerve system resident immune cells participate in the neuroinflammatory microenvironment that contributes to dopaminergic neurons loss in the substantia nigra. Understanding the phenotype switch of microgliosis in PD could help to identify the molecular mechanism which could attenuate or delay the progressive decline in motor function. KCa3.1 has been reported to regulate the "pro-inflammatory" phenotype switch of microglia in neurodegenerative pathological conditions.Methods: We here investigated the effects of gene deletion or pharmacological blockade of KCa3.1 activity in wild-type or KCa3.1(-/-) mice after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mouse model of PD. MPTP-induced PD mouse model was subjected to the rotarod test to evaluate the locomotor ability. Glia activation and neuron loss were measured by immunostaining. Fluo-4 AM was used to measure cytosolic Ca2+ level in 1-methyl-4-phenylpyridinium (MPP+)-induced microgliosis in vitro.Results: We report that treatment of MPTP-induced PD mouse model with gene deletion or pharmacological blockade of KCa3.1 with senicapoc improves the locomotor ability and the tyrosine hydroxylase (TH)-positive neuron number and attenuates the microgliosis and neuroinflammation in the substantia nigra pars compacta (SNpc). KCa3.1 involves in store-operated Ca2+ entry-induced Ca2+ overload and endoplasmic reticulum stress via the protein kinase B (AKT) signaling pathway during microgliosis. Gene deletion or blockade of KCa3.1 restored AKT/mammalian target of rapamycin (mTOR) signaling both in vivo and in vitro.Conclusions: Taken together, these results demonstrate a key role for KCa3.1 in driving a pro-inflammatory microglia phenotype in PD.