Lack of genetic evidence for NLRP3 inflammasome involvement in Parkinson’s disease pathogenesis

作者：Konstantin Senkevich, Lang Liu, Chelsea X. Alvarado, Hampton L. Leonard, Mike A. Nalls, Global Parkinson’s Genetics Program (GP2), Ziv Gan-Or · 发表于：npj Parkinson s Disease · 年份：2024 · DOI：10.1038/s41531-024-00744-9 · 被引用次数：13 · 研究领域：Inflammasome and immune disorders、Adenosine and Purinergic Signaling、Genetics and Neurodevelopmental Disorders

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.