GPNMB is a biomarker for lysosomal dysfunction and is secreted via LRRK2-modulated lysosomal exocytosis

Genome-wide association studies have identified <i>Glycoprotein Nmb</i> (<i>GPNMB</i>) as a risk factor for Parkinson's disease. The risk allele increases <i>GPNMB</i> transcription and GPNMB protein levels in the CSF highlighting GPMNB as a potential biomarker for Parkinson's disease. However, a lack of knowledge of GPNMB's function and mechanism of secretion has hindered an interpretation of secreted GPNMB levels. In this study, we assessed the mechanism of GPNMB secretion by macrophages, the primary cell type expressing GPNMB in the brain. We show that GPNMB is secreted in response to lysosomal stress via lysosomal exocytosis and highlight the Parkinson's disease risk factor LRRK2 as a strong modulator of GPNMB secretion.