Science (New York, N.Y.) · 2022
GPNMB confers risk for Parkinson's disease through interaction with α-synuclein.
СтатьяНазвание и аннотация: Перевод в очереди
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Diaz-Ortiz Maria E, Seo Yunji, Posavi Marijan, Carceles Cordon Marc, Clark Elisia, Jain Nimansha, Charan Rakshita, Gallagher Michael D, Unger Travis L, Amari Noor, Skrinak R Tyler, Davila-Rivera Roseanne, Brody Eliza M, Han Noah, Zack Rebecca, Van Deerlin Vivianna M, Tropea Thomas F, Luk Kelvin C, Lee Edward B, Weintraub Daniel, Chen-Plotkin Alice S
Аннотация
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.