“Gut is where it all starts and so does Parkinson’s”

Any neurologist will tell you: Parkinson’s disease is a neurological condition. The most noticeable symptoms of Parkinson’s disease—uncontrollable tremors, sluggish mobility, and the sensation that one’s feet are glued to the ground—all result from the loss of neurons in an area of the brain that controls movement. However, many researchers believe that the neurodegenerative condition may begin in the gut, years before the first neurological symptoms show.

New research by Columbia University researchers David Sulzer, Ph.D., Dritan Agalliu, Ph.D., and two of their graduate students adds to the evidence supporting this concept, indicating that what causes the earliest gastrointestinal alterations in Parkinson’s disease may be a misdirected immune onslaught.

Sulzer added by saying, “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,”

The gut and autoimmunity:

Sulzer became interested in the gut-first explanation of Parkinson’s disease because his own studies pointed to the role of an inflammatory response in Parkinson’s.

In Parkinson’s disease, a protein called alpha-synuclein misfolds, accumulates inside neurons, and gradually kills them. Sulzer’s lab, in partnership with immunologists at the La Jolla Institute of Immunology, discovered that minute amounts of misfolded alpha-synuclein might emerge on the exterior of neurons, making them exposed to immune system attack. The immunological onslaught may be causing greater acute harm to the neurons than the internal alpha synuclein aggregates.

In this context Sulzer also mentioned that “The blood of Parkinson’s patients often contains immune cells that are primed to attack the neurons but it’s not clear where or when they are primed.”

The gut was an intriguing possibility since it has the same neurons as the brain and because most Parkinson’s patients have constipation years before the disease is diagnosed. Sulzer collaborated with Agalliu, a neuroimmunologist with experience in mouse models of another neurological condition with autoimmune aspects (multiple sclerosis), to investigate this possibility.

Gut symptoms are caused by the immune response to alpha synuclein. Francesca Garretti and Connor Monahan, graduate students directed by Agalliu and Sulzer, first created a mouse capable of displaying pieces of misfolded alpha-synuclein on cell surfaces (natural mice do not have this ability). They next injected alpha-synuclein into the mice and observed what happened in the brain and intestines.

The researchers found no signs of Parkinson’s disease in the brain, but they did find that an immune attack on neurons in the gut caused constipation and other gastrointestinal symptoms similar to those seen in most Parkinson’s patients years before they are diagnosed.

Sulzer added on, “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 “

The findings also open the potential that early detection – and then blockage – of an immune response in the gut could prevent a subsequent attack on the brain’s neurons, effectively halting Parkinson’s disease.

Need: A mouse with Parkinson’s disease

However, it is unclear how important the immune system is in the Parkinson’s brain at the moment. If the researchers can figure out why the brains of their mice did not acquire any signs of Parkinson’s, the answer to that question may become clearer.

The research hypothesizes that immune cells are not reaching the brain in their mouse model because the animals are young and age has not yet reduced the blood-brain barrier sufficiently to allow immune cells to pass through. Opening the barrier or hastening the aging process may result in mice developing gastrointestinal and neurological problems.

“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.” says Sulzer

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