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 microgl

SUBMITTER: Carceles-Cordon M 

PROVIDER: S-EPMC12870591 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature