Francisco Ciruela, professor at the Faculty of Medicine and Health Sciences of the UB and member of the Institute of Neurosciences (UBNeuro) and IDIBELL, explains that “what the study suggests is that this biomarker could be used to define whether the progression of the disease will be fast or slow. On a clinical scale, being able to perform this stratification is very important, because the management of patients with slowly progressive Parkinson’s disease versus those with rapid progression involves a different clinical approach.”

According to the researcher, patients with rapid progression have an accelerated onset and worsening of symptoms, motor fluctuations and complications, as well as an increased likelihood of cognitive impairment and psychiatric symptoms. In contrast, patients with slow progression have a gradual onset and progression of symptoms and can maintain higher levels of functional ability and for longer periods of time. In addition, they often have milder symptoms, especially in the early stages. “If the disease progresses rapidly, the prognosis is worse than if it progresses slowly, as it can be managed more like a chronic disease. Consequently, patients with a rapid progression require more complex clinical management than those with a slow progression, who have a better prognosis,” says the UB professor, who led the study.

Researchers from the Spanish National Cancer Research Centre (CNIO); the Institute for Biomedical Research and Innovation in Cadiz; the Karolinska Institute (Sweden); the University of California (USA); and King’s College London (UK) also participated in the study.

Study with patient samples from different neurodegenerative diseases

This research follows a 2021 study by the same research team, which found that ecto-GPR37, present on neuronal cells in the brain, could be a promising candidate diagnostic biomarker for Parkinson’s disease. Ecto-GPR37 is a fragment of an orphan neuronal G protein-coupled receptor called GPR37. Although it is a Parkinson’s-associated receptor, neither its neuronal function nor the endogenous ligand, i.e. the specific molecule to which it binds, is yet known.

To validate previous findings and test whether this potential biomarker is specific to Parkinson’s disease, the researchers have now analysed the processing of GPR37 in the brain and the presence of ecto-GPR37 in the cerebrospinal fluid of patients with Parkinson’s, Alzheimer’s and also other neurodegenerative diseases with clinical features similar to Parkinson’s, such as multiple system atrophy, corticobasal degeneration and progressive supranuclear palsy. The researchers note that, “despite the similarities, patients with these diseases have a different prognosis and do not respond to levodopa, the main treatment for Parkinson’s disease. Therefore, the exploration of new biomarkers is essential to accurately stratify patients, especially in the early stages, when the diagnosis is more challenging.”

The results of this analysis show that ecto-GPR37 levels were only increased in patients with slowly progressive Parkinson’s disease, and not in the fast type or in the other pathologies. “This finding suggests a possible connection between the processing and expression of GPR37 and the speed of disease progression,” says Francisco Ciruela.

According to the scientists, the most plausible explanation for the presence of ecto-GPR37 in the brain is that when the GPR37 receptor reaches the surface of neurons, it fragments and releases ecto-GPR37 outside the cell. As a result of this processing, in this type of slowly progressive Parkinsonism, ecto-GPR37 would circulate in higher concentrations in the cerebrospinal fluid, the fluid that surrounds the brain and spinal cord.

On the other hand, researchers have also described a differential pattern of GPR37 processing and expression in the other neurodegenerative diseases analysed. “This underlines the potential usefulness of GPR37 as well for distinguishing between different neurodegenerative conditions,” adds the UB professor.

European-wide multicentre study

Although the results obtained by the UB and IDIBELL team are very promising, the researchers point out that the biomarker role of ecto-GPR37 should be validated in a larger cohort of patients from different hospitals to confirm its clinical utility, establish its robustness and ensure its applicability as a prognostic tool in disease progression. Ciruela notes that “now the next step would be to develop and implement a multicentre clinical project on a European scale that will allow us to carry out the validation study with Parkinson’s patients, which is necessary to move towards clinical application.”

Moreover, the researchers, thanks to funding from the Michael J. Fox Foundation, have recently adapted an assay to determine the presence of ecto-GPR37 in blood samples from patients, “which makes it much easier to determine analytically,” they conclude.