Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
Science. 2022 Aug 19;377(6608):eabk0637. doi: 10.1126/science.abk0637.
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 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 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, represents a PD risk gene with potential for biomarker development and therapeutic targeting.
许多帕金森病（PD）的风险基因座已通过全基因组关联研究（GWAS）确定，但靶基因和机制在很大程度上仍然未知。我们通过对表达数量性状基因座和 PD 风险信号的共定位分析，将 GWAS 衍生的染色体 7 基因座（哨兵单核苷酸多态性 rs199347）与 联系起来，这一结果在人类大脑中的等位基因特异性表达研究中得到了证实。在细胞中，糖蛋白非转移性黑色素瘤蛋白 B（GPNMB）与α-突触核蛋白（aSyn）共免疫沉淀并共定位。在诱导多能干细胞衍生的神经元中， 缺失导致内化 aSyn 原纤维和形成 aSyn 病理学的能力丧失。在 731 个 PD 和 59 个对照生物样本中，PD 血浆中 GPNMB 升高，与疾病严重程度相关。因此， 代表了一个具有潜在生物标志物开发和治疗靶点的 PD 风险基因。
