Unexpected origins of Parkinson’s disease revealed

An autoimmune reaction in mice to a protein linked to Parkinson’s disease damaged neurons in the digestive tract, adding to evidence that the disease may start in the gut. Photo credit: David Sulzer, Columbia University Irving Medical Center

Ask any neurologist and they’ll tell you: Parkinson’s disease is a disorder of the brain. The obvious signs of this disease, such as involuntary shaking, decreased movement speed, and the feeling of the feet sticking to the ground, arise from the loss of neurons in the area of ​​the brain responsible for regulating movement.

However, a growing number of scientists are of the opinion that this neurodegenerative condition may have its roots in the gut, potentially appearing long before any neurological symptoms appear.

New findings by Columbia University researchers David Sulzer, PhD, and Dritan Ajalio, PhD, and two of their graduate students add to the evidence supporting this hypothesis — and show that what triggers the primary gastrointestinal changes in Parkinson’s disease can be wrong. In directing an immune attack.

“If this is the beginning of Parkinson’s disease in many people, it’s likely that we can identify who has the disease before it reaches the brain and, hopefully, stop it in its tracks,” says Sulzer. The new findings were recently published in the journal nervous cells.

Autoimmunity and the intestine

The gut-first theory of Parkinson’s disease, originally proposed 20 years ago, began to intrigue Sulzer after his own research pointed to a role for the autoimmune response in Parkinson’s.

In Parkinson’s disease, a protein called alpha-synuclein becomes unfolded, builds up inside nerve cells, and slowly poisons the cells. Sulzer’s lab, in collaboration with immunologists at the La Jolla Institute of Immunology, has shown that small fragments of unfolded alpha-synuclein can also appear on the outer surface of neurons, making the neurons vulnerable to attack from the immune system. An immune attack can cause more severe damage to neurons than endogenous deposits of alpha-synuclein.

“The blood of Parkinson’s patients often contains immune cells that are primed to attack neurons, but it is not clear where or when they are primed,” Sulzer says.

The gut was an interesting possibility because it contains the same neurons and because most Parkinson’s patients suffer from constipation years before brain symptoms appear and the disease is diagnosed. To pursue this hypothesis, Sulzer teamed up with Agalio, a neuroimmunologist with experience in mouse models of another neurological disorder (multiple sclerosis) with autoimmune features.

The immune response to alpha-synuclein causes symptoms in the gut

To see if an immune reaction to alpha-synuclein can trigger the onset of disease, Francesca Garrity and Connor Monahan, graduate students directed by Agaleo and Sulzer, created a mouse capable of displaying unfolded pieces of alpha-synuclein on cell surfaces. (Normal mice do not have this ability.) Then they injected alpha-synuclein into the mice and watched what happened in the brain and gut.

The researchers did not see any signs of Parkinson’s disease in the brain, but they did see that an immune attack on nerve cells in the gut leads to constipation and other gastrointestinal effects similar to those seen in most Parkinson’s patients years before they are diagnosed with the disease.

“This shows that an autoimmune reaction can lead to what appear to be the early stages of Parkinson’s disease, which strongly supports that Parkinson’s disease is in part an autoimmune disease,” says Sulzer.

The findings also raise the possibility that early detection – and then interruption – of the immune response in the gut could prevent a later attack on neurons in the brain and stop Parkinson’s disease in its tracks.

Wanted: A rat with Parkinson’s disease

However, it is not currently clear how large a role the immune system plays in the brain of Parkinson’s patients. The answer to this question may become clearer if researchers discover why the brains of their mice show no signs of Parkinson’s disease.

The team hypothesizes that immune cells in their mouse model may not reach the brain because the animals are young and the blood-brain barrier has not yet weakened enough to allow immune cells to take hold. Opening the septum or accelerating the aging process could cause the mice to develop gastrointestinal and brain symptoms.

“Our ultimate goal is to develop a model of Parkinson’s disease in mice that recreates the disease process in humans, which is not currently in place,” says Sulzer. “This will be crucial in answering questions about the disease that we cannot explore in humans and ultimately in developing better treatments.”

Reference: “Interaction of the α-synuclein Loop with HLA-DRB1∗15:01 Leads to Intestinal Features in Mice Reminiscent of Initial Parkinson’s Disease” by Francesca Garetti, Connor Monahan, Nicholas Sloane, Jamie Bergen, Sanjid Shahryar, Seon-woo Kim, Alessandro Sitt, Tyler Cutforth, Elaine Kanter, Dritan Agalio and David Sulzer, August 18, 2023, Available Here. nervous cells.
doi: 10.1016/j.neuron.2023.07.015

This research was funded by Aligning Science Across Parkinson’s through the Michael J. Fox Foundation for Parkinson’s Disease Research. National Institutes of Health; JPB Foundation; The National Multiple Sclerosis Society, gifts from Newport Equities LLC, the Walz family, and the PANDAS Network to the Department of Neurology at Columbia University.