Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Blvd, Memphis TN 38105, USA.
Department of Neurosciences, Jefferson Hospital for Neuroscience, Thomas Jefferson University, 900 Walnut St, Philadelphia PA 19107, USA.
Brain. 2018 Jun 1;141(6):1753-1769. doi: 10.1093/brain/awy077.
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.
LRRK2 基因中的错义突变导致迟发性帕金森病。LRRK2 基因突变在人类和帕金森病 LRRK2 小鼠模型中的不完全外显率表明，该疾病可能是由遗传易感性和持续的外源刺激的复杂相互作用引起的。由于神经炎症通常与帕金森病的发病机制有关，我们研究了突变 LRRK2 在体内调节免疫反应和炎症信号的潜在作用。在这里，我们表明，表达人类致病性 LRRK2 突变的小鼠，但不是野生型小鼠或表达人类野生型 LRRK2 的小鼠，表现出长期脂多糖诱导的黑质神经元丢失。这种神经退行性变伴随着大脑中炎症的加剧。突变小鼠大脑中增强的免疫反应随后通过诱导神经元内 LRRK2 的上调对神经元产生影响。然而，增强的神经炎症不太可能是由功能失调的小胶质细胞或浸润的 T 细胞和/或单核细胞触发的，而是由外周循环的炎症分子触发的。外周免疫细胞中细胞因子动力学和炎症途径的分析表明，LRRK2 突变改变了 II 型干扰素免疫反应，表明这种增强的神经炎症反应可能发生在中枢神经系统之外。总的来说，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变调节中起着意想不到但重要的作用，并为干扰疾病的发作和进展提供了新的靶点。
