The orphan G protein-coupled receptor 37 (GPR37), widely associated with Parkinson's disease (PD), undergoes proteolytic processing under physiological conditions. Its N-terminus is proteolyzed by a disintegrin and metalloproteinase 10 (ADAM-10), which generates various membrane receptor forms and the shedding of the ectodomain in the extracellular environment. Here, we investigate the processing and density of GPR37 in several neurodegenerative conditions, including Lewy body disease (LBD), multiple system atrophy (MSA), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD). An increase in receptor processing was observed exclusively in the early stages of LBD in both the PFC and the striatum, two key brain areas involved in neurodegeneration. In contrast, in MSA only the 52 kDa GPR37 specific form was shown in the striatum. This form was also elevated in the PFC and striatum of AD necropsies. On the contrary, the processing of GPR37 remained unaffected in the brain of patients with CBD and PSP. Furthermore, while the content of ecto-GPR37 increased in the CSF of PD patients, in MSA, CBD and PSP subjects the levels were not altered. Importantly, within patients with PD, those who showed rapid progression of the disease did not have elevated levels of ecto-GPR37 in the CSF, while those who slowly progressed showed a significant increase, suggesting a possible prognostic use of ecto-GPR37 in PD. This research underscores the distinctive processing and density patterns of GPR37 in neurodegenerative diseases, offering crucial insights into its potential role as a predictor of PD progression rates.