GPNMB protein (Glycoprotein Nonmetastatic Melanoma Protein B, also known as Osteoactivin or DC-HIL) is a type I transmembrane glycoprotein encoded by the [GPNMB](/genes/gpnmb) gene. GPNMB is highly expressed in [microglia](/cell-types/microglia), macrophages, osteoclasts, and melanocytes, where it functions as an anti-inflammatory receptor, phagocytosis mediator, and neuroprotective factor. In the context of neurodegeneration, GPNMB is strongly upregulated in disease-associated [microglia](/cell-types/microglia-neuroinflammation) (DAM) and lipid-laden microglia in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and [ALS](/diseases/amyotrophic-lateral-sclerosis). GPNMB is a top GWAS hit for PD risk, and its soluble ectodomain (sGPNMB) serves as both a cerebrospinal fluid biomarker and a neuroprotective signaling molecule.
GPNMB is massively upregulated in substantia nigra microglia in PD patients
sGPNMB levels are elevated in PD CSF and correlate with disease severity
[α-Synuclein](/proteins/alpha-synuclein) aggregates induce GPNMB in activated microglia
sGPNMB promotes neuronal survival through ERK/AKT signaling
[GBA1](/genes/gba1) mutations (Gaucher/PD overlap) drive lysosomal stress and GPNMB induction
Alzheimer's Disease
GPNMB is a hallmark marker of disease-associated microglia (DAM) — the microglial phenotype found around amyloid plaques
GPNMB+ microglia show enhanced phagocytic capacity but also contribute to chronic inflammation when overwhelmed
sGPNMB levels are elevated in AD CSF and plasma
GPNMB expression correlates with [TREM2](/genes/trem2) and [APOE](/genes/apoe) expression in plaque-associated microglia
ALS
GPNMB is upregulated in spinal cord microglia of ALS patients and SOD1-G93A mice
sGPNMB may serve as a CSF biomarker for microglial activation in ALS
GPNMB promotes phagocytic clearance of motor neuron debris
Gaucher Disease
[GBA1](/genes/gba1)-deficient macrophages massively upregulate GPNMB due to glucosylceramide accumulation
GPNMB is one of the most elevated proteins in Gaucher disease serum
The GBA1-GPNMB axis connects lysosomal storage disorders to PD risk
Therapeutic Targeting
sGPNMB as a therapeutic: Recombinant sGPNMB ectodomain administration is neuroprotective in PD models
Anti-GPNMB antibodies: Glembatumumab vedotin (CDX-011) targets GPNMB-expressing cells in cancer; repurposing for neuroinflammation is under investigation
GPNMB as a biomarker: CSF and plasma sGPNMB levels track microglial activation and may serve as pharmacodynamic biomarkers for anti-inflammatory therapies
[Moloney EB et al., The glycoprotein GPNMB is selectively elevated in the substantia nigra of Parkinson disease patients and increases after lysosomal stress (2018) (2018)](https://doi.org/10.1016/j.nbd.2018.04.013)
[Nalls MA et al., Identification of novel risk loci, causal insights, and heritable risk for Parkinson disease: a meta-analysis of genome-wide association studies (2019) (2019)](https://doi.org/10.1016/S1474-4422(19)
[Hüttenrauch M et al., Glycoprotein NMB: a novel Alzheimer's disease associated marker expressed in a subset of activated microglia (2018) (2018)](https://doi.org/10.1186/s40478-018-0508-2)
[Keren-Shaul H et al., A unique microglia type associated with restricting development of Alzheimer's disease (2017) (2017)](https://doi.org/10.1016/j.cell.2017.05.018)
[Zigdon H et al., Identification of a biomarker panel for improvement of Gaucher disease diagnosis (2015) (2015)](https://doi.org/10.1016/j.ymgme.2014.12.001)
[Tanaka H et al., The potential of GPNMB as novel neuroprotective factor in the central nervous system (2012) (2012)](https://doi.org/10.2174/156720212803530591)