Abstract: G protein–coupled receptor 37 (GPR37) is an orphan receptor predominantly expressed in the brain, particularly in oligodendrocytes and certain types of neurons. Notably, it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions, resulting in the formation of cleaved receptor forms and the release of its ectodomain (ecto-GPR37) into the extracellular milieu (Mattila et al., 2021). Importantly, ecto-GPR37 density is increased in cerebrospinal fluid (CSF) of patients suffering from sporadic Parkinson’s disease (PD), together with an abnormal GPR37 processing in post-mortem PD substantia nigra (Morató et al., 2021; Figure 1A). Recently, we demonstrated that GPR37 density upregulation extends to other key brain regions, concretely the prefrontal cortex and striatum (Figure 1B), during the early stages of the disease, but not to other neurodegenerative disorders with overlapping symptoms, including c o r t i c o b a s a l d e g e n e r a t i o n , p r o g r e s s i v e supranuclear palsy, and multiple system atrophy (Argerich et al., 2024). However, the most striking finding was that the increase in GPR37 density was accompanied by elevated levels of CSF ecto-GPR37, observed exclusively in patients with slow-progressing PD. Thus, these results suggest that GPR37 has a differential regulation on PD pathology. Indeed, ecto-GPR37 might serve as a biomarker for predicting disease progression rates (Argerich et al., 2024). In summary, GPR37 has emerged as a potential marker for the postmortem stratification of neurodegenerative diseases, while ecto-GPR37 shows promise as a predictive biomarker for the progression of PD (Morató et al., 2021; Argerich et al., 2024).