New Evidence Suggests Parkinson's Starts in the Gut

A recent study supports the hypothesis that Parkinson's disease originates in the gut, finding that a misdirected immune attack could trigger the initial gastrointestinal changes seen in the condition. 

The study, published in the journal Neuron, was led by David Sulzer, PhD, and Dritan Agalliu, PhD, both researchers at Columbia University Irving Medical Center in New York City. Inspired by the gut-first theory of Parkison’s disease originally proposed 20 years ago, Sulzer, whose own research focuses on the role of an autoimmune response in the development of Parkinson’s, teamed up with Agalliu and two of their undergraduate students to explore the connect between the gut, the immune system, and Parkinson’s.

According to researchers, in Parkinson’s, a protein called alpha-synuclein becomes misfolded, accumulates inside neurons, and slowly poisons cells. Sulzer’s previous research has shown that small portions of the misfolded alpha-synuclein can also be found on the outside of neurons, leaving the neurons vulnerable to an immune system attack. 

"The blood of Parkinson's patients often contains immune cells that are primed to attack the neurons," said Sulzer, "but it's not clear where or when they are primed."

To determine whether an immune reaction to alpha-synuclein can trigger Parkison’s, the researchers developed a mice model capable of displaying pieces of misfolded alpha-synuclein on cell surfaces, something normal mice cannot do. The mice were injected with alpha-synuclein, and then researchers monitored what happened in their brain and gut.

While the researchers saw no signs of resembling Parkinson’s disease in the brain, an immune attack on neurons in the gut caused constipation and other gastrointestinal effects like those seen in most Parkinson’s patients years before their diagnosis.

According to Sulzer, these results suggest that an autoimmune reaction may lead to the early stages of Parkinson’s. "If this is the beginning of Parkinson's in many people, we could potentially identify who has the disease before it ever reaches the brain and hopefully stop it in its tracks," he said.

In future investigations, Sulzer hopes to find out why the brains of the mice did not develop any signs of Parkinson's. Sulzer and his team hypothesized that immune cells in their mouse models did not reach the brain because they were young, and their blood-brain barrier was not yet weak enough to let immune cells through.

"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," Sulzer said. "That will be critical in answering questions about the disease that we can't explore in people and eventually developing better therapies."