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Lack of genetic evidence for NLRP3 inflammasome involvement in Parkinson’s disease pathogenesis
npj Parkinson's Disease ( IF 6.7 ) Pub Date : 2024-08-05 , DOI: 10.1038/s41531-024-00744-9
Konstantin Senkevich 1, 2 , Lang Liu 1, 2, 3 , Chelsea X Alvarado 4, 5 , Hampton L Leonard 4, 5, 6 , Mike A Nalls 4, 5 , , Ziv Gan-Or 1, 2, 3
Affiliation  

Activation of the NLRP3 inflammasome has been implicated in Parkinson’s disease (PD) based on in vitro and in vivo studies. Clinical trials targeting the NLRP3 inflammasome in PD are ongoing. However, the evidence supporting NLRP3’s involvement in PD from human genetics data is limited. We analyzed common and rare variants in NLRP3 inflammasome-related genes in PD cohorts, performed pathway-specific polygenic risk score (PRS) analyses, and studied causal associations using Mendelian randomization (MR) with the NLRP3 components and the cytokines IL-1β and IL-18. Our findings showed no associations of common or rare variants, nor of the pathway PRS with PD. MR suggests that altering the expression of the NLRP3 inflammasome, IL-1β, or IL-18, does not affect PD risk or progression. Therefore, our results do not support a role for the NLRP3 inflammasome in PD pathogenesis or as a target for drug development.



中文翻译:


缺乏 NLRP3 炎性体参与帕金森病发病机制的遗传证据



根据体外和体内研究,NLRP3 炎性体的激活与帕金森病 (PD) 有关。针对 PD 中 NLRP3 炎性体的临床试验正在进行中。然而,人类遗传学数据支持 NLRP3 参与 PD 的证据有限。我们分析了 PD 队列中 NLRP3 炎症体相关基因的常见和罕见变异,进行了通路特异性多基因风险评分 (PRS) 分析,并使用孟德尔随机化 (MR) 研究了 NLRP3 成分以及细胞因子 IL-1β 和 IL 的因果关系-18。我们的研究结果显示,常见或罕见变异以及 PRS 通路与 PD 没有关联。 MR 表明,改变 NLRP3 炎性体、IL-1β 或 IL-18 的表达不会影响 PD 风险或进展。因此,我们的结果不支持 NLRP3 炎症小体在 PD 发病机制中的作用或作为药物开发的靶点。

更新日期:2024-08-05
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