Computational, cell biological, and human tissue-based studies establish GPNMB as a risk gene and potential therapeutic target for Parkinson's Disease (PD), researchers report. PD is a debilitating progressive neurodegenerative brain disorder that affects millions of people worldwide. Diagnosis of the disease often relies on the presence of motor control symptoms that generally begin to appear after decades of disease progression. Thus, there is an urgent need to not only better understand the pathology of PD but also develop a panel of biomarkers that could identify individuals' risk for developing PD before significant neurodegeneration occurs.
Although genome-wide association studies (GWAS) have identified more than 80 genetic loci that contribute to risk for PD, the target genes and the biological mechanisms associated with them remain largely unexplored. To date, pathways related to a-synuclein (aSyn) – the main component of disease-defining neuropathological lesions – have been investigated as a potential therapeutic target. However, these efforts have not yet been fruitful. Maria Diaz-Ortiz and colleagues evaluated one PD GWAS risk locus on chromosome 7 and linked it to the transmembrane protein Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB).
Using a variety of experimental approaches, Diaz-Ortiz et al. discovered that GPNMB was found to interact with aSyn and that, in cells, was both necessary and sufficient for uptake of fibrillar forms of aSyn and subsequent development of aSyn pathology. What's more, the authors found that there were increased concentrations of GPNMB in plasma samples from nearly 800 early symptomatic and advanced PD patients and that the concentrations increased with disease stage. This finding suggests that GPNMB could be a valuable biomarker for disease progression. In a Perspective, Brit Mollenhauer and Christine Von Arnim discuss the study and its findings further.
Diaz-Ortiz, M.E., et al. (2022) GPNMB confers risk for Parkinson’s disease through interaction with α-synuclein. Science. doi.org/10.1126/science.abk0637.