The glycoprotein GPNMB is selectively elevated in the substantia nigra of Parkinson's disease patients and increases after lysosomal stress

GPNMB is a glycoprotein observed upon tissue damage and inflammation and is associated with astrocytes, microglia, and macrophages. Gene variations in GPNMB are linked with Parkinson's disease (PD) risk, and changes in protein levels of GPNMB have been found in lysosomal storage disorders, including Gaucher's disease with glucocerebrosidase (GCase) deficiency. In the current study, GPNMB increases were seen in the substantia nigra (SN) of PD patients compared to age-matched controls. Such PD patients have a decrease in GCase activity and corresponding elevation of glycosphingolipids in the SN (Rocha et al., 2015a). Interestingly, transgenic mice modelling synucleinopathy did not show GPNMB elevations or altered GCase activity levels compared to wildtype mice. However, upon CBE-induced GCase lysosomal dysfunction with elevated glycosphingolipids in wildtype mice, there were similar changes in GPNMB levels in the brain as seen in PD patient brains. These results indicate that GPNMB levels do not depend on alpha-synuclein load per se but relate directly to the lipidopathy changes induced by CBE-mediated GCase inhibition. The experimental modelling of elevating glycolipids resulted in GPNMB elevations with glial activation in several brain regions in mice. This is the first demonstration of region-specific elevations of GPNMB protein in Parkinson's disease. The presence of GPNMB in PD patient substantia nigra, the induction of GPNMB after experimental glycosphingolipid increases, but not with pure alpha-synucleinopathy, point towards the potential for primary lipid-induced degeneration in PD.