Researchers at Columbia University, led by David Sulzer, PhD, and Dritan Agalliu, PhD, along with their graduate students, have unveiled intriguing new insights linking Parkinson’s disease to gut health. While Parkinson’s is traditionally viewed as a brain disorder, mounting evidence suggests that its origins may lie in the gastrointestinal system and may manifest years before the first neurological symptoms become apparent.
Sulzer and his team have been investigating the role of an autoimmune response in Parkinson’s disease. In Parkinson’s, a protein called alpha-synuclein becomes misfolded and accumulates inside neurons, causing gradual cell damage. Their research has revealed that fragments of this misfolded alpha-synuclein can also appear on the surface of neurons, rendering them susceptible to immune system attacks, possibly causing more immediate harm than the internal protein deposits.
“The blood of Parkinson’s patients often contains immune cells that are primed to attack the neurons,” explains Sulzer, “but it’s not clear where or when they are primed.”
This autoimmune aspect of the disease led researchers to explore the gut as a potential starting point for Parkinson’s. Notably, the gut contains neurons similar to those found in the brain, and most Parkinson’s patients experience constipation long before they exhibit neurological symptoms. To delve deeper into this theory, Sulzer partnered with neuroimmunologist Dritan Agalliu, who specializes in mouse models of autoimmune neurological disorders.
To investigate whether an immune response to alpha-synuclein can trigger Parkinson’s and where it occurs, graduate students Francesca Garretti and Connor Monahan, under the guidance of Agalliu and Sulzer, engineered mice capable of displaying misfolded alpha-synuclein fragments on cell surfaces—an ability natural mice lack. They then injected alpha-synuclein into these mice and closely monitored changes in both their brains and gastrointestinal systems.
Surprisingly, the researchers did not observe any brain-related signs resembling Parkinson’s disease. However, they did find that an immune assault on neurons in the gut resulted in constipation and other gastrointestinal symptoms akin to those experienced by most Parkinson’s patients several years before formal diagnosis.
Sulzer remarks, “This shows that an autoimmune reaction can lead to what appears to be the early stages of Parkinson’s and is strong support that Parkinson’s is in part an autoimmune disease.“
These findings open up the possibility of early detection and intervention in the gut to prevent future attacks on brain neurons, potentially halting the progression of Parkinson’s disease.
However, one critical question remains: why did the mice’s brains not exhibit Parkinson’s symptoms? The researchers speculate that the immune cells in their mouse model might not have reached the brain due to the animals’ youth. Aging typically weakens the blood-brain barrier, allowing immune cells to pass through. Thus, modifying the barrier or accelerating the aging process in the mice might yield subjects that develop both gastrointestinal and brain symptoms.
Sulzer states, “Our ultimate goal is to develop a model of Parkinson’s disease in mice that recreates the human disease process, which doesn’t exist right now. That will be critical in answering questions about the disease that we can’t explore in people and eventually developing better therapies.”
These groundbreaking findings offer a promising avenue for further research and potentially novel strategies to combat Parkinson’s disease, a condition that has long eluded a definitive cure.
-A Balanced Brain is a Better Brain for a Happier Life-