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

doi:10.1038/s41531-024-00744-9

. 2024 Aug 5;10(1):145.

doi: 10.1038/s41531-024-00744-9.

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

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}; Global Parkinson’s Genetics Program (GP2); Ziv Gan-Or^{7

8

9}

Affiliations

¹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada.
² Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada.
³ Department of Human Genetics, McGill University, Montréal, QC, Canada.
⁴ Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20814, USA.
⁵ Data Tecnica, Washington, DC, 200373, USA.
⁶ DZNE Tübingen, Tübingen, Germany.
⁷ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada. ziv.gan-or@mcgill.ca.
⁸ Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada. ziv.gan-or@mcgill.ca.
⁹ Department of Human Genetics, McGill University, Montréal, QC, Canada. ziv.gan-or@mcgill.ca.

PMID: 39103393
PMCID: PMC11300440
DOI: 10.1038/s41531-024-00744-9

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

Konstantin Senkevich et al. NPJ Parkinsons Dis. 2024.

. 2024 Aug 5;10(1):145.

doi: 10.1038/s41531-024-00744-9.

Authors

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}; Global Parkinson’s Genetics Program (GP2); Ziv Gan-Or^{7

8

9}

Affiliations

¹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada.
² Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada.
³ Department of Human Genetics, McGill University, Montréal, QC, Canada.
⁴ Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20814, USA.
⁵ Data Tecnica, Washington, DC, 200373, USA.
⁶ DZNE Tübingen, Tübingen, Germany.
⁷ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada. ziv.gan-or@mcgill.ca.
⁸ Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada. ziv.gan-or@mcgill.ca.
⁹ Department of Human Genetics, McGill University, Montréal, QC, Canada. ziv.gan-or@mcgill.ca.

PMID: 39103393
PMCID: PMC11300440
DOI: 10.1038/s41531-024-00744-9

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.

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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.

Figures

**Fig. 1. Locus zoom plot of *NLRP3*, *CASP1*, *PYCARD, IL-1β,* and *IL-18* genes (±500 kb) in Parkinson’s disease GWAS.**
The SNP with the lowest P-value in the studied gene or locus is highlighted by red square. The punctuated line represents GWAS level of significance p < 5 × 10⁻⁸. SNPs shown in gray are below this significance level, while those in blue exceed it. X axis: Chromosomal position (in Mb). Y axis: Negative log10 of the P-values from GWAS.

**Fig. 2. Pathway-specific PRS analysis of NLRP3 inflammasome genes.**
OR odds ratio, CI confidence interval, PPMI Parkinson’s Progression Markers Initiative, APDGC Autopsy-confirmed Parkinson Disease GWAS Consortium, IPDGC International Parkinson Disease Genomics Consortium, NINDS National Institute of Neurological Disorders and Stroke Repository Parkinson’s Disease Collection, NGRC NeuroGenetics Research Consortium, UKBB UK Biobank.

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Update of

Lack of genetic evidence for NLRP3-inflammasome involvement in Parkinson's disease pathogenesis.
Senkevich K, Liu L, Alvarado CX, Leonard HL, Nalls MA; Global Parkinson’s Genetics Program (GP2); Gan-Or Z. Senkevich K, et al. 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.

References

1. Jewell, S., Herath, A. M. & Gordon, R. Inflammasome activation in Parkinson’s disease. J. Parkinsons Dis.12, S113–s128 (2022). 10.3233/JPD-223338 - DOI - PMC - PubMed
1. Haque, M. E. et al. Targeting the microglial NLRP3 inflammasome and its role in Parkinson’s disease. Mov. Disord.35, 20–33 (2020). 10.1002/mds.27874 - DOI - PubMed
1. Codolo, G. et al. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PloS One8, e55375 (2013). 10.1371/journal.pone.0055375 - DOI - PMC - PubMed
1. Gustot, A. et al. Amyloid fibrils are the molecular trigger of inflammation in Parkinson’s disease. Biochem. J.471, 323–333 (2015). 10.1042/BJ20150617 - DOI - PubMed
1. Shao, Q. H., Zhang, X. L., Yang, P. F., Yuan, Y. H. & Chen, N. H. Amyloidogenic proteins associated with neurodegenerative diseases activate the NLRP3 inflammasome. Int. Immunopharmacol.49, 155–160 (2017). 10.1016/j.intimp.2017.05.027 - DOI - PubMed

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[1] Jewell, S., Herath, A. M. & Gordon, R. Inflammasome activation in Parkinson’s disease. J. Parkinsons Dis.12, S113–s128 (2022). 10.3233/JPD-223338 - DOI - PMC - PubMed

[2] Jewell, S., Herath, A. M. & Gordon, R. Inflammasome activation in Parkinson’s disease. J. Parkinsons Dis.12, S113–s128 (2022). 10.3233/JPD-223338 - DOI - PMC - PubMed

[3] Haque, M. E. et al. Targeting the microglial NLRP3 inflammasome and its role in Parkinson’s disease. Mov. Disord.35, 20–33 (2020). 10.1002/mds.27874 - DOI - PubMed

[4] Haque, M. E. et al. Targeting the microglial NLRP3 inflammasome and its role in Parkinson’s disease. Mov. Disord.35, 20–33 (2020). 10.1002/mds.27874 - DOI - PubMed

[5] Codolo, G. et al. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PloS One8, e55375 (2013). 10.1371/journal.pone.0055375 - DOI - PMC - PubMed

[6] Codolo, G. et al. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PloS One8, e55375 (2013). 10.1371/journal.pone.0055375 - DOI - PMC - PubMed

[7] Gustot, A. et al. Amyloid fibrils are the molecular trigger of inflammation in Parkinson’s disease. Biochem. J.471, 323–333 (2015). 10.1042/BJ20150617 - DOI - PubMed

[8] Gustot, A. et al. Amyloid fibrils are the molecular trigger of inflammation in Parkinson’s disease. Biochem. J.471, 323–333 (2015). 10.1042/BJ20150617 - DOI - PubMed

[9] Shao, Q. H., Zhang, X. L., Yang, P. F., Yuan, Y. H. & Chen, N. H. Amyloidogenic proteins associated with neurodegenerative diseases activate the NLRP3 inflammasome. Int. Immunopharmacol.49, 155–160 (2017). 10.1016/j.intimp.2017.05.027 - DOI - PubMed

[10] Shao, Q. H., Zhang, X. L., Yang, P. F., Yuan, Y. H. & Chen, N. H. Amyloidogenic proteins associated with neurodegenerative diseases activate the NLRP3 inflammasome. Int. Immunopharmacol.49, 155–160 (2017). 10.1016/j.intimp.2017.05.027 - DOI - PubMed

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

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

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