Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies

ABSTRACT Glycoprotein nonmetastatic melanoma B (GPNMB), encoded by the target gene ( GPNMB ) of a Parkinson’s disease (PD) risk locus, acts as a secreted factor mediating inflammatory effects in the context of immunity and cancer. In a neurodegenerative disease context, GPNMB is critical to cellular uptake of pathological forms of alpha-synuclein (aSyn), the hallmark disease protein that misfolds and accumulates in PD. Here, we demonstrate that the non-membrane-anchored, extracellular domain of GPNMB, shed into conditioned medium or added as recombinant protein, enables uptake of aSyn fibrils in a non-cell-autonomous manner. In human postmortem brain, GPNMB is widely expressed in neurons and microglia, with increased microglial expression in the setting of neurodegenerative disease. In microglial cell lines and induced pluripotent stem cell-derived microglia (iMicroglia), GPNMB expression and secretion increases with exposure to apoptotic neurons. In the aSyn-fibril seeded model of PD, iMicroglia-derived GPNMB allows for development of aSyn pathology in GPNMB knockout neurons, while conditioned medium from GPNMB knockout iMicroglia lacks this effect. Conversely, treatment with anti-GPNMB antibodies rescues neurons from development of aSyn pathology in this model. Finally, in 1675 human postmortem cases, GPNMB genotypes conferring higher GPNMB expression associate with more widespread aSyn pathology, without affecting beta-amyloid or tau pathology. Taken together, our data suggest a positive feedback model, where neuronal death triggers increased GPNMB expression and secretion by microglia, leading to increased uptake of pathological forms of aSyn by neurons, leading to more neuronal death. Importantly, this cycle can be interrupted by anti-GPNMB antibodies, offering an avenue for therapeutic development. One Sentence Summary The extracellular domain of GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies. Highlights The extracellular domain of GPNMB confers capacity for uptake of alpha-synuclein fibrils to iPSC-derived neurons (iNeurons) lacking GPNMB expression. GPNMB is widely expressed in neurons and microglia in human brain, with more expression in microglia, particularly in Parkinson’s disease brain. iPSC-derived microglia (iMicroglia) secrete GPNMB in response to neurodegeneration-related insults, and iMicroglia-derived GPNMB enhances development of alpha-synuclein pathology in iNeurons. Anti-GPNMB antibodies rescue iNeurons from development of synuclein pathology. Expression quantitative trait loci (eQTLs) for GPNMB associate with extent of alpha-synuclein pathology in human neurodegenerative disease.