In 5-10% of all people with Parkinson's disease, a hereditary cause of the disease can be identified. Some of these genes have been identified in recent years by special DNA analyses of the entire genome. The best known Parkinson's-associated gene is called SNCA. Its mutated form was first discovered in 1997 in a large Italian family. The mutation is inherited in an autosomal dominant manner and results in a structural change in the protein encoded by SNCA, α-synuclein.
In a new study published last year by Diaz-Ortiz and colleagues in Science, additional point mutations, known as single nucleotide polymorphisms (SNPs), were found to increase production of the glycoprotein non-metastatic melanoma protein B (GPNMB), which is associated with an increased risk of Parkinson's disease. GPNMB increases in the serum of patients and correlates with disease severity. It could therefore be a new biomarker for disease progression. In principle, biomarkers are used to identify individuals with an increased risk of disease before the onset of symptoms. In the case of Parkinson's, for example, this is the amount of α-synuclein in the cerebrospinal fluid, in addition to a reduction in dopamine transporters in the brain.
GPNMB is a transmembrane glycoprotein that was first described in 1995 and is increasingly expressed in metastatic melanoma cell lines. The extracellular, outward-facing domain can be cleaved, whereupon the soluble fragment diffuses freely and binds to cellular receptors, which then trigger diverse responses. Back in 2016, GPNMB was found to be elevated in the brains of patients suffering from Gaucher disease. This lysosomal storage disorder is caused by mutations in the glucocerebrosidase (GBA) gene, which is also a risk factor for Parkinson's disease. GBA mutations can lead to loss of glucocerebrosidase activity and lysosomal dysfunction, resulting in accumulation of α-synuclein and other proteins in lysosomes.
Increased concentrations of GPNMB have also been found in postmortem brain samples from patients with Parkinson's disease or from Alzheimer's disease patients. The concentration of GPNMB in CSF generally correlates with aging, but also with phosphorylated tau, a marker for Alzheimer's disease. Thus, the protein is not specific for Parkinson's disease (nor was there an increase in GPNMB in the CSF of the patients).
In addition, the authors of the study were able to demonstrate the functional significance of GPNMB in the context of inflammatory processes, as it reduces the secretion of pro-inflammatory cytokines in macrophages, and the protein is also found in microglia. To analyze the function of GPNMB in neurons in more detail, GPNMB was removed in human induced pluripotent stem cells (iPSCs) that differentiated into neurons. In the synapses of these neurons, α-synuclein was only detectable at a reduced level. Interestingly, α-synuclein forms a direct bond with GPNMB. Therefore, in cells lacking GPNMB, uptake (internalization) of α-synuclein fibrils no longer occurred. Furthermore, in cells with low GPNMB expression, which do not normally internalize fibrillar synuclein, the increase in GPNMB was sufficient for synuclein to be taken up again.
Taken together, these experiments demonstrate that GPNMB is required for the intercellular transport of fibrillar α-synuclein and the subsequent development of typical synuclein pathology. However, it remains an open question whether the increased expression of GPNMB is also causally related to neuronal degeneration.
References:
Diaz-Ortiz ME, Seo Y, Posavi M, ... , Weintraub D, Chen-Plotkin AS (2022) GPNMB confers risk for Parkinson's disease through interaction with α-synuclein. Science 377:eabk0637
Mollenhauer B, von Arnim CAF (2022) Toward preventing Parkinson's disease. Science 377:818
Image credit: iStock/Dr_Microbe
Comments