Gut protein misfolding may spot Parkinson’s years before symptoms

Routine gut biopsies may turn up evidence of protein misfolding, predicting the risk of developing neurodegenerative diseases such as Parkinson’s disease years before neurological symptoms appear, a study suggested.

Researchers from the University of Aberdeen, NHS Grampian, and NHS Highland found that more than half of people who had digestive symptoms but no diagnosed neurological disease had a condition called protein misfolding enteropathy (PME). PME predicted disease with greater than 80% sensitivity and was linked to neurologic symptom onset nearly seven years later.

“The study highlights the urgent need for better detection tools for neurodegenerative diseases,” Jenna Gregory, PhD, professor at the University of Aberdeen and lead author of the study, said in a university news story. “Many of these conditions still lack effective treatment options, making early detection and scalable screening approaches especially important for improving patient outcomes.”

The study, “Protein misfolding enteropathy predicts and prognosticates 2 neurodegenerative disease years before symptom onset,” was published in Gastroenterology. It was funded by NHS Grampian Charity, Target ALS, and LifeArc.

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Accumulation of misfolded proteins is a common hallmark of neurodegenerative diseases, including Parkinson’s, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS), thought to contribute to the progressive loss of nerve cells. In Parkinson’s, the buildup of toxic clumps of misfolded alpha-synuclein is believed to contribute to the death of nerve cells that produce dopamine, a signaling molecule involved in motor control.

By the time Parkinson’s symptoms appear, substantial nerve cell loss has already occurred, and therapies are usually less effective. “Early intervention strategies aligned with readily accessible targets for biomarker development are urgently needed for these diseases,” the researchers wrote.

The team focused on PME, as gastrointestinal symptoms often precede neurological symptoms in certain neurodegenerative conditions. They retrospectively analyzed gut biopsies from 196 people (53.1% women, median age 70) with unexplained gastrointestinal symptoms, followed for a median of 14 years to track the development of neurodegenerative diseases. The team assessed three key proteins associated with neurodegeneration: alpha-synuclein, TDP-43, and tau.

Evidence of PME was detected in 60% of cases. Almost half of the participants (46%) had alpha-synuclein aggregates, 34% had TDP-43 aggregates, and 5% tau deposition. Also, 40% of the participants had aggregates of only one misfolded protein (alpha-synuclein or TDP-43), 20% PME of more than one misfolded protein, and 40% had none.

“Our findings suggest that routine clinical samples, such as gastrointestinal biopsies, could be repurposed to identify individuals at high risk of dementia,” said Angus Watson, MD, clinical chair of surgery and professor at Aberdeen. “This could transform how we approach prevention trials and the development of disease-modifying therapies.”

During follow-up, 37% of participants developed neurological symptoms after a median of nearly seven years, “many years earlier than we previously recognized,” Gregory said. PME was strongly associated with the later development of neurodegenerative diseases.

Those with PME were significantly more likely to develop Parkinson’s and dementia with Lewy bodies, with PME presence demonstrating over 80% sensitivity in predicting disease. However, the ability to detect negative cases was lower than 50%, “indicating that absence of [protein misfolding in the gut] does not exclude future neurological disease,” the researchers wrote.

Survival analysis indicated that participants with two or three misfolded protein types had significantly lower survival than those without such proteins. There was no effect of age at the time of biopsy or sex differences on the presence or absence, or the number of, misfolded proteins.

“We are seeing clear evidence that the same pathological protein changes that occur in several neurodegenerative diseases can occur in the gut many years earlier than we previously recognized,” Gregory said. “This opens up entirely new possibilities for early detection and intervention.”

If the findings are validated in larger studies, gut-based biomarkers could become a widely accessible tool for identifying at-risk individuals and monitoring treatment responses, the researchers said.

“With incidences of neurodegenerative diseases increasing, research like this which shines the spotlight on early diagnosis and intervention is becoming even more important,” said Lisa Duthie, NHS Grampian Charity lead.