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

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.

Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease

“…Most clusters, particularly clusters 6 and 7, also expressed several genes involved in phagocytosis ( Cd68 ), whereas activated clusters expressed genes involved in lymphocyte chemotaxis ( Ccl5 ), and remodeling of the extracellular matrix ( Mmp14 ) (Figure 4b-c). Furthermore, they most highly expressed Gpnmb , a gene that has been genetically implicated in PD and had high expression of several DAM defining genes such as Apoe, Lgals3 , and Fabp5 (Figure 4c, Supplemental Figure 4a) [19, 21-23]. As previously seen in the DAMs, pseudotime analysis using monocle3 suggested that these two clusters likely represented differential stages of activation (Supplemental Figure 4b).…”

A Mitochondrial Inside-Out Iron-Calcium Signal Reveals Drug Targets for Parkinson’s Disease

“…We performed size exclusion chromatography (SEC), where protein complexes with higher molecular weight (MW) are eluted faster than those with lower MW, using lysates of HEK cells treated by Fe 2+ , Ca 2+ , or H2O2. Detecting MCU from cell lysates using SEC has been successfully shown (Dong et al, 2017;Lambert et al, 2019;Tomar et al, 2016). We found that Fe 2+ , Ca 2+ , and H2O2 treatment all shifted the MCU elution peaks to the earlier fractions with higher-order oligomers than control (Figure 5A-E; anti-MCU was validated in Figure S4C).…”

“…The enhanced mitochondrial Ca 2+ -uptake observed in PD neurons (Figure 4A) led us to investigate the Ca 2+ -uptake channel in the IMM-MCU. Because MCU oligomerization is essential for MCU's function to import Ca 2+ into the mitochondria (Dong et al, 2017;Fan et al, 2018;Fan et al, 2020), we explored the possibility that MCU oligomerization was affected by Fe 2+ , Ca 2+ , or ROS, small molecules elevated in PD neuronal mitochondria (Figure 4). We performed size exclusion chromatography (SEC), where protein complexes with higher molecular weight (MW) are eluted faster than those with lower MW, using lysates of HEK cells treated by Fe 2+ , Ca 2+ , or H2O2.…”

“…More than 90% of the PD cases are considered sporadic with no known causal mutations. Genome-wide association studies (GWAS) have identified over 90 risk loci (Diaz-Ortiz et al, 2022). Functional studies on known causal genes of familial patients and from cellular and animal PD models have pointed to 2 Mitochondria are the center of cellular metabolism and communication.…”

Single-cell Mendelian randomisation identifies cell-type specific genetic effects on human brain disease and behaviour

“…As a further illustration of the translational value of directionality and cell-type context, we associate increased expression of GPNMB (encoding glycoprotein nonmetastatic melanoma protein B) in astrocytes and oligodendrocyte precursor cells (OPCs) with an increased risk of Parkinson’s disease (PD) (MR P =3.01×10 −6 and P =1.68×10 −8 respectively). This directionality of effect was recently independently confirmed by the experimental demonstration that loss of GPNMB activity results in loss of cellular internalization of fibrillar alpha synuclein and reduced pathogenicity, confirming GPNMB inhibition as a candidate therapeutic strategy in PD[29]. Similarly, epidermal growth factor receptor (EGFR) was recently suggested as an AD risk gene following genomic fine mapping based on bulk brain-tissue cis- eQTL reference datasets[30].…”