In the run-up to Parkinson’s disease, some sufferers show behavioral abnormalities during the nocturnal REM sleep phase. A new study now shows that aggregates of misfolded alpha-synuclein proteins can be detected in the stool of these people. These clumps of protein have previously been linked to the development of Parkinson’s disease. The detection method in stool samples could open up a new possibility for non-invasive early detection.
Misfolded alpha-synuclein proteins play a key role in Parkinson’s disease. In the brain, aggregates of these proteins can damage dopamine-producing nerve cells and thus contribute to the typical Parkinson’s symptoms with motor and mental disorders. However, studies have shown that in around 30 percent of those affected, Parkinson’s does not first develop in the brain, but in the nervous system of the intestine. In this so-called body-originating Parkinson’s disease, the harmful protein aggregates migrate via nerve tracts from the intestines to the brain and then cause damage there.
New test could help with early detection
Although alpha-synuclein aggregates have long been discussed as potential biomarkers for developing Parkinson’s disease, it has so far been difficult to reliably detect them in body fluids. A team led by Anja Schaffrath from Forschungszentrum Jülich has now developed a test method that makes it possible to identify the misfolded proteins and the resulting clumps in stool samples.
As part of their study, the team set up a biobank of more than 200 stool samples – including 94 samples from Parkinson’s patients, 51 from healthy controls and 72 samples from people suffering from what is known as isolated REM sleep behavior disorder (iRBD). This disease is known as a precursor to Parkinson’s disease originating in the body and is associated with the fact that those affected move a lot during their vivid, often aggressive dreams, sometimes endangering themselves and others. So far, iRBD has usually been diagnosed using extensive questionnaires and examinations in the sleep laboratory.
Misfolded proteins detectable in the stool
With the help of the newly developed test method, Schaffrath and her team examined the stool samples of all subjects for alpha-synuclein aggregates. The result: “We were the first to detect alpha-synuclein aggregates in the stool,” reports Schaffrath’s colleague Gültekin Tamgüney. “This proves that the protein aggregates can actually get into the stool from the affected nerve cells in the gastrointestinal tract and that they can be detected with the help of our test.”
Schaffrath and her team found the significantly increased level of alpha-synuclein aggregates in the stool primarily in iRBD patients. “This could help to develop a non-invasive early detection test,” say the researchers. However, the sensitivity and specificity of the current test method are still relatively low. When comparing healthy people and iRBD patients, the test correctly identified around three quarters of the patients as having the disease. However, he also incorrectly classified around half of the healthy as sick. “Sensitivity and specificity could be improved in the future by including additional biomarkers,” according to the team of authors.
No synuclein in “normal” Parkinson’s patients
To the surprise of the researchers, no differences between healthy and Parkinson’s patients could be determined based on the alpha-synuclein concentration in the stool. Earlier studies had shown that significantly increased concentrations of the misfolded proteins can be detected in the liquor of Parkinson’s patients. However, none of this showed up in the chair. From the researchers’ point of view, one possible explanation could be that they could not determine with certainty whether the Parkinson’s patients included in the study had developed in their intestines or in their brains. Protein aggregates in the stool are only to be expected in patients with the body-origin variant.
Another explanation could be that the protein aggregates are excreted with the stool, especially in the early phase of the disease, for reasons that have not yet been clarified. In future studies, the researchers want to take a closer look at the course and mechanisms of the disease. In the long term, this could help to find ways of early detection and early therapy for Parkinson’s and other diseases associated with misfolded alpha-synuclein proteins.
Source: Anja Schaffrath (Jülich Research Center) et al., npj Parkinson’s Disease, doi: 10.1038/s41531-023-00458-4