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Cited by 158Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNeurological disorders and treatments

GPNMB confers risk for Parkinson’s disease through interaction with α-synuclein

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Diaz-Ortiz, Maria E., Seo, Yunji, Posavi, Marijan, Carceles Cordon, Marc, Clark, Elisia, Jain, Nimansha, Charan, Rakshita, Gallagher, Michael D. +13 more·2022·Science
DOI 10.1126/science.abk0637PMC PMC9870036
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Abstract

Many risk loci for Parkinson’s disease (PD) have been identified by genome-wide association studies (GWASs), but target genes and mechanisms remain largely unknown. We linked the GWAS-derived chromosome 7 locus (sentinel single-nucleotide polymorphism rs199347) to GPNMB through colocalization analyses of expression quantitative trait locus and PD risk signals, confirmed by allele-specific expression studies in the human brain. In cells, glycoprotein nonmetastatic melanoma protein B (GPNMB) coimmunoprecipitated and colocalized with α-synuclein (aSyn). In induced pluripotent stem cell–derived neurons, loss of GPNMB resulted in loss of ability to internalize aSyn fibrils and develop aSyn pathology. In 731 PD and 59 control biosamples, GPNMB was elevated in PD plasma, associating with disease severity. Thus, GPNMB represents a PD risk gene with potential for biomarker development and therapeutic targeting.

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  • GPNMB's potential role in PD pathogenesis and links to aggregation of α-synuclein has recently been highlighted.

    “Its potential role in PD pathogenesis and links to aggregation of α‐synuclein has recently been highlighted (Diaz‐Ortiz et al, 2022).”

    From The genetic regulation of protein expression in cerebrospinal fluid (2023) · cites this paper as Diaz‐Ortiz et al, 2022

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Authors
Diaz-Ortiz, M. E., Seo, Y., Posavi, M., Carceles Cordon, M., Clark, E., Jain, N., Charan, R., Gallagher, M. D., Unger, T. L., Amari, N., Skrinak, R. T., Davila-Rivera, R., Brody, E. M., Han, N., Zack, R., Van Deerlin, V. M., Tropea, T. F., Luk, K. C., Lee, E. B., Weintraub, D., & Chen-Plotkin, A. S.
Affiliations
  • Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • University of Pennsylvania (US)
  • Washington University in St. Louis (US)
  • Flagship Pioneering (United States) (US)
  • Whitehead Institute for Biomedical Research (US)
  • Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Philadelphia VA Medical Center (US)
Corresponding author
Seo, Yunji
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-08-19
Volume
377
Issue
6608
Pages
eabk0637-eabk0637
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.abk0637
PMC
PMC9870036
OpenAlex
W4292680960
Cited by
158
References
6
Citations by year
2026: 36 · 2025: 44 · 2024: 29 · 2023: 37 · 2022: 12
FWCI
16.05
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (U19AG062418, P30AG072979)
  • National Institute of Neurological Disorders and Stroke (F31NS113481, K23NS114167, P50NS053488, R01NS115139, R01NS082265)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
Keywords
Parkinson's disease, GPNMB, alpha-synuclein, genetic susceptibility loci, chromosome 7, protein-protein interaction, iPSC-derived neurons, plasma biomarkers, disease severity, risk genes
MeSH terms
Brain, Humans, Membrane Glycoproteins, Parkinson Disease, Polymorphism, Single Nucleotide, alpha-Synuclein, Genome-Wide Association Study

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