Lack of genetic evidence for NLRP3 inflammasome involvement in Parkinson's disease pathogenesis
- PMID: 39103393
- PMCID: PMC11300440
- DOI: 10.1038/s41531-024-00744-9
Lack of genetic evidence for NLRP3 inflammasome involvement in Parkinson's disease pathogenesis
Abstract
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.
© 2024. The Author(s).
Conflict of interest statement
Z.G.O. received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanquabio Guidepoint, Lighthouse and Deerfield. C.X.A., M.A.N., and H.L.L.’s participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board for Character Bio Inc. and as an advisor to Neuron23 Inc. The remaining authors declare no competing interests.
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Update of
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Lack of genetic evidence for NLRP3-inflammasome involvement in Parkinson's disease pathogenesis.medRxiv [Preprint]. 2024 May 30:2023.09.20.23295790. doi: 10.1101/2023.09.20.23295790. medRxiv. 2024. Update in: NPJ Parkinsons Dis. 2024 Aug 5;10(1):145. doi: 10.1038/s41531-024-00744-9. PMID: 37886468 Free PMC article. Updated. Preprint.
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