Protein Fragment in CSF Shows Potential as Diagnostic Biomarker

A protein fragment known as GPR37 is evident in the cerebrospinal fluid of people with Parkinson’s disease, and may be promising candidate as a biomarker for earlier diagnosis, scientists in Spain announced.

This fragment at high levels was found to be specific to the cerebrospinal fluid (CSF; the liquid surrounding the brain and spinal cord) of Parkinson’s patients, as opposed to those with Alzheimer’s, another neurodegenerative disease, researchers with the Bellvitge Biomedical Research Institute at the University of Barcelona reported.

Their study “Ecto-GPR37: a potential biomarker for Parkinson’s disease,” was published in the journal Translational Neurodegeneration.

Although potential diagnostic biomarkers have been studied in Parkinson’s, none to date have shown an ability to be clinically useful.

GPR37 is a fragment of a G protein-coupled receptor expressed in several brain regions, and whose function in nerve cells is not completely understood. In certain cases of parkinsonism, an insoluble form of GPR37 is known to accumulate at toxic levels in the brain, suggesting a possible role of this receptor in Parkinson’s disease.

These neuroscientists assessed the expression of GPR37 in cases of sporadic Parkinson’s disease, investigating if it could be a suitable biomarker for Parkinson’s.

Their study included 41 patients (mean age of 64, mean disease duration of 5.8 years), and 45 age- and sex-matched volunteers with benign neurological diagnoses such as tension headache (mean age, 64) as a control group. Twelve of the patients were not taking dopaminergic therapies for their disease.

Parkinson’s patients underwent neurological exams, including evaluations of their motor and non-motor symptoms. CSF samples were collected from all study participants to determine the presence of GPR37 protein fragments (peptides), also called ecto-GPR37.

“Unlike the brain, we can access the cerebrospinal fluid much more easily. Cerebrospinal fluid is a mirror of what happens in the nervous system,” Francisco Ciruela, PhD, the study’s lead investigator, said in a press release.

The levels of ecto-GPR37, GPR37 protein and messenger RNA were also assessed in post-mortem CSF and brain samples from eight people with Parkinson’s (mean age, 71.4) and eight age-matched controls (mean age 66.8). Similar post-mortem samples  of 23 people with Alzheimer’s disease (mean age 67.6) and 22 matched controls (mean age, 65.7) were collected from the Clinical Dementia Center of Göttingen, in Germany, and evaluated. Of note, messenger RNA or mRNA is the molecule generated from DNA and used as the template for protein production.

Results showed GPR37 density and mRNA expression to significantly higher in brain tissue of sporadic Parkinson’s patients compared with controls. Increased amounts of ecto-GPR37 peptides were also observed in the CSF of Parkinson’s patients.

When researchers looked at the levels of total alpha-synuclein — a protein that builds in the brain of Parkinson’s patients — in post-mortem CSF samples, they did not find a difference between these patients and controls.

Importantly, the amount of GPR37 mRNA and ecto-GPR37 in Alzheimer’s post-mortem samples were unchanged, suggesting that GPR37 is a highly specific biomarker for Parkinson’s disease.

“In this study, we reported, for the first time, that significantly higher levels of ecto-GPR37 were detectable in the CSF of PD [Parkinson’s disease] patients,” the researchers wrote, adding this finding “provides strong evidence supporting CSF ecto-GPR37 as a promising biomarker of PD.”

These results, however, must be validated in a larger group of patients before they might be of clinical use, they added.

“Further longitudinal studies combining CSF ecto-GPR37 with reliable biomarkers for neurodegenerative diseases are needed,” the team wrote.

Ciruela and his team, together with researchers at the Karolinska Institute, were awarded a €125,033 (about $147,000), three-year research grant by The Michael J. Fox Foundation to further investigate this potential biomarker’s detection limits, specificity, and sensitivity.