Missense mutations in the leucine rich repeat kinase 2 (LRRK2) gene result in late-onset Parkinson's disease. The incomplete penetrance of LRRK2 mutations in humans and LRRK2 murine models of Parkinson's disease suggests that the disease may result from a complex interplay of genetic predispositions and persistent exogenous insults. Since neuroinflammation is commonly associated with the pathogenesis of Parkinson's disease, we examine a potential role of mutant LRRK2 in regulation of the immune response and inflammatory signalling in vivo. Here, we show that mice overexpressing human pathogenic LRRK2 mutations, but not wild-type mice or mice overexpressing human wild-type LRRK2 exhibit long-term lipopolysaccharide-induced nigral neuronal loss. This neurodegeneration is accompanied by an exacerbated neuroinflammation in the brain. The increased immune response in the brain of mutant mice subsequently has an effect on neurons by inducing intraneuronal LRRK2 upregulation. However, the enhanced neuroinflammation is unlikely to be triggered by dysfunctional microglia or infiltrated T cells and/or monocytes, but by peripheral circulating inflammatory molecules. Analysis of cytokine kinetics and inflammatory pathways in the peripheral immune cells demonstrates that LRRK2 mutation alters type II interferon immune response, suggesting that this increased neuroinflammatory response may arise outside the central nervous system. Overall, this study suggests that peripheral immune signalling plays an unexpected-but important-role in the regulation of neurodegeneration in LRRK2-associated Parkinson's disease, and provides new targets for interfering with the onset and progression of the disease.

中文翻译：

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突变体 LRRK2 介导导致体内神经变性的外周和中枢免疫反应。

富含亮氨酸重复激酶 2 (LRRK2) 基因的错义突变导致迟发性帕金森病。人类和 LRRK2 小鼠帕金森病模型中 LRRK2 突变的不完全外显率表明，该疾病可能是遗传易感性和持续外源性损伤的复杂相互作用所致。由于神经炎症通常与帕金森病的发病机制相关，我们研究了突变 LRRK2 在调节体内免疫反应和炎症信号传导中的潜在作用。在这里，我们显示过度表达人类致病性 LRRK2 突变的小鼠，而不是野生型小鼠或过度表达人类野生型 LRRK2 的小鼠表现出长期脂多糖诱导的黑质神经元损失。这种神经变性伴随着大脑中加剧的神经炎症。突变小鼠大脑中增加的免疫反应随后通过诱导神经元内 LRRK2 上调对神经元产生影响。然而，增强的神经炎症不太可能由功能失调的小胶质细胞或浸润的 T 细胞和/或单核细胞触发，而是由外周循环炎症分子触发。外周免疫细胞中细胞因子动力学和炎症通路的分析表明，LRRK2 突变改变了 II 型干扰素免疫反应，表明这种增加的神经炎症反应可能出现在中枢神经系统之外。总体而言，这项研究表明，外周免疫信号在 LRRK2 相关帕金森病的神经退行性调节中起着意想不到但重要的作用，