Lack of genetic evidence for NLRP3 inflammasome involvement in Parkinson’s disease pathogenesis
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.
Authors
- Konstantin Senkevich (ORCID: https://orcid.org/0000-0003-3407-5716)
- Chelsea X. Alvarado (ORCID: https://orcid.org/0000-0002-5973-7512)
- Hampton L. Leonard (ORCID: https://orcid.org/0000-0003-2390-8110)
- Lang Liu (ORCID: https://orcid.org/0000-0002-0348-2258)
- Mike A. Nalls
Institutions
- Montreal Neurological Institute and Hospital (CA)
- National Institutes of Health (US)
- Data Tecnica International (United States) (US)
- National Institute of Neurological Disorders and Stroke (US)
- McGill Genome Centre (CA)
- Bernstein Center for Computational Neuroscience Tübingen (DE)
- National Institute on Aging (US)
- McGill University (CA)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2024-08-05
- DOI
- https://doi.org/10.1038/s41531-024-00744-9
- Citations
- 9
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 2.10
Funders
- U.S. Department of Health and Human Services
- Michael J. Fox Foundation for Parkinson's Research
- McGill University
- Compute Canada
- Parkinson Study Group
- Consortium canadien en neurodégénérescence associée au vieillissement
- Parkinson Canada
- Canada First Research Excellence Fund
- National Institutes of Health
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke