Bogacki, E. C. | bioRxiv Science

bioRxiv2025

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

Genome-wide association studies have identified Glycoprotein Nmb (GPNMB) as a risk factor for Parkinsons Disease. The risk allele increases GPNMB transcription and GPNMB protein levels in the CSF highlighting GPMNB as a potential biomarker for Parkinsons Disease. However, a lack of knowledge of GPNMBs function and mechanism of secretion have 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 Parkinsons Disease risk factor LRRK2 as a strong modulator of GPNMB secretion.

cell biology↗

bioRxiv2023

Mutations in GPNMB associated with Amyloid cutis dyschromica alter intracellular trafficking and processing of GPNMB

Amyloid cutis dyschromica (ACD) is a rare skin condition characterized by focal areas of hyperpigmentation with hypopigmented macules and distinct regions of amyloid deposition. Until recently, the genetic cause of ACD remained unknown. Several studies have since named GPNMB truncation mutations as causal, with protein loss-of-function underlying ACD pathogenesis. GPNMB missense mutations have also been observed in patients, but these are less well characterized; especially on a cellular level. Here, we observed that GPNMB missense mutations implicated in familial ACD show distinct cellular phenotypes that result in impaired protein maturation and processing from the endoplasmic reticulum (ER) to the trans-Golgi network (TGN), prompting failed trafficking to lysosomes. These missense mutations also show failed secretion of the extracellular fragment of GPNMB, a well-characterized property of the protein. Overall, this work highlights previously undescribed cellular characteristics of GPNMB missense mutations implicated in ACD and helps to better inform the clinically observed phenotypes, as well as underscore GPNMBs role at melanosomes.

cell biology↗