研究人员通过表达定量性状位点和帕金森病（PD）风险信号的共定位分析，将全基因组关联研究（GWAS）得出的7号染色体位点（哨兵单核苷酸多态性rs199347）与GPNMB联系起来，并由人脑中的等位基因特异性表达研究证实。在细胞中，糖蛋白非转移性黑色素瘤蛋白B（GPNMB）与α-synuclein（aSyn）共免疫沉淀和共定位。在诱导多能干细胞衍生的神经元中，GPNMB的损失导致失去内吞aSyn纤维的能力，并出现aSyn病理。在731个PD和59个对照生物样本中，PD血浆中的GPNMB升高，与疾病的严重程度有关。因此，GPNMB代表了一个PD风险基因，并具有开发为生物标志物和治疗靶标的潜力。
据悉，GWAS已经确定了许多PD的风险位点，但靶标基因和机制在很大程度上仍然未知。
附：英文原文
Title: GPNMB confers risk for Parkinson’s disease through interaction with α-synuclein
Author: Maria E. Diaz-Ortiz, Yunji Seo, Marijan Posavi, Marc Carceles Cordon, Elisia Clark, Nimansha Jain, Rakshita Charan, Michael D. Gallagher, Travis L. Unger, Noor Amari, R. Tyler Skrinak, Roseanne Davila-Rivera, Eliza M. Brody, Noah Han, Rebecca Zack, Vivianna M. Van Deerlin, Thomas F. Tropea, Kelvin C. Luk, Edward B. Lee, Daniel Weintraub, Alice S. Chen-Plotkin
Issue&Volume: 2022-08-19
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.
DOI: abk0637
Source: https://www.science.org/doi/10.1126/science.abk0637