ABSTRACT Leucine rich-repeat kinase 2 (LRRK2) is involved in the pathogenesis of Parkinson’s disease (PD). LRRK2 has kinase and GTPase activities, and mediates several cell functions, including vesicle trafficking, apoptosis, autophagy, mitochondrial dynamics, and neuroinflammation. G2019S (GS) is the most prevalent mutation of LRRK2. The mutation increases kinase activity, suggesting that this activity is crucial for PD pathogenesis. The activation and inhibition of LRRK2 kinase increases and reduces the levels of proinflammatory cytokines, respectively suggesting that the role of LRRK2 in neuroinflammation is critical for the pathology of PD. Previously, we demonstrated that microglial activation by lipopolysaccharide (LPS) increases mitochondrial fission via the activation of LRRK2 kinase, while LRRK2 kinase inhibition diminishes the fission morphology and release of tumor necrosis factor-alpha (TNFα) in BV2 or rat primary microglia and the brains of GS transgenic mice. In this study, the ectopic expression of GS LRRK2 in BV2 cells significantly elevated the expression of Drp1 along the fragmented mitochondria and decreased mitochondria size compared with controls. GS LRRK2-transfected BV2 cells displayed significantly increased TNFα release and neuronal death. Inhibition of LRRK2 kinase alleviated these features. TNFα levels in brains of GS mice were significantly increased compared to those in their littermates. These data further support our previous findings concerning LPS-induced neuroinflammation and mitochondrial fission in microglia via LRRK2 kinase activation.

中文翻译：

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G2019s LRRK2 促进线粒体裂变并增加 TNFα 介导的神经炎症反应

摘要 富含亮氨酸重复激酶 2 (LRRK2) 参与帕金森病 (PD) 的发病机制。LRRK2 具有激酶和 GTPase 活性，并介导多种细胞功能，包括囊泡运输、细胞凋亡、自噬、线粒体动力学和神经炎症。G2019S (GS) 是 LRRK2 最普遍的突变。该突变增加了激酶活性，表明该活性对于 PD 发病机制至关重要。LRRK2 激酶的激活和抑制分别增加和降低促炎细胞因子的水平，表明 LRRK2 在神经炎症中的作用对于 PD 的病理学至关重要。以前，我们证明脂多糖（LPS）激活小胶质细胞通过激活 LRRK2 激酶增加线粒体裂变，而 LRRK2 激酶抑制减少了 BV2 或大鼠原代小胶质细胞和 GS 转基因小鼠大脑中肿瘤坏死因子-α (TNFα) 的裂变形态和释放。在这项研究中，与对照相比，BV2 细胞中 GS LRRK2 的异位表达显着提高了沿碎片化线粒体的 Drp1 表达并减小了线粒体大小。GS LRRK2 转染的 BV2 细胞显示出显着增加的 TNFα 释放和神经元死亡。LRRK2 激酶的抑制减轻了这些特征。与同窝小鼠相比，GS 小鼠大脑中的 TNFα 水平显着增加。这些数据进一步支持了我们之前关于通过 LRRK2 激酶激活在小胶质细胞中 LPS 诱导的神经炎症和线粒体裂变的发现。