Two new studies are shedding light on how alpha-synuclein (αS), a protein connected to Parkinson's disease, contributes to the development of the disease.
Research papers providing the studies’ findings both explore the protein’s role in the body’s immune response, offering up new insights into what causes Parkinson’s.
These findings also provide possibilities on how to better detect and treat the disease.
The GI infection link
A study published in the Journal of Innate Immunity found that acute and chronic upper gastrointestinal (GI) tract infections seem to be linked to Parkinson's disease.
According to researchers at Georgetown University Medical Center, along with collaborators at the National Institutes of Health (NIH) and other institutions, upper GI tract infections release αS.
This causes a naturally occurring immune response. But when infections are regular or chronic, they may inhibit the body from clearing αS, which may lead to developing the disease.
Dr. Michael Zasloff, professor of surgery and pediatrics at Georgetown University School of Medicine, and scientific director of the MedStar Georgetown Transplant Institute, said scientists already knew that αS accumulation is tied to Parkinson’s.
Prior to performing the research, Zasloff said researchers thought αS was a “bad player,” but it’s actually good because it is produced when the nervous system detects a potential pathogen.
When the protein is secreted into tissues, it attracts white blood cells that can neutralize the pathogen.
“By this means the nerve can protect both itself and the surrounding tissues,” he told Healthline.
But too much αS, which can occur with regular infections, can become toxic to the system.
“If the nervous system makes too much αS, its concentration inside nerves reaches a point where the protein aggregates. These aggregates are very nasty, since they provoke inflammation and can physically damage cells. Too much of a good thing causes Parkinson’s disease,” he said.
A protective protein gone awry
Zasloff’s team assessed biopsies from 42 children with upper GI issues, as well as 14 people who had norovirus — a common cause of upper GI infections — who had received intestinal transplants.
They found that αS in enteric nerves of the upper GI tract in the children was linked to the degree of acute and chronic inflammation in the intestinal wall.
Some transplant patients showed αS while they had norovirus. Researchers say that human αS may attract human immune cells and activate dendritic cells to alert the immune system about the protein, driving the immune response that can cause damage.
“We observed that in these kids the more inflammation, the more intense the presence of αS in the nerves. We also could show that when a person contracted … norovirus, αS accumulated in the nervous tissues of their duodenum, not having been present before the infection,” Zasloff told Healthline.
In a nutshell, his report shows that GI infections produce αS as part of a normal immune response.
Zasloff noted that the protein is also present in the brains of people who have Alzheimer’s, and in the spinal cords of people who develop ALS, prompting the question of whether Alzheimer’s and ALS could be provoked by an infection.
In the meantime, Zasloff is starting a clinical trial of the drug ENT-01, which is a synthetic version of squalamine, a natural steroid found in the dogfish shark.
The drug is looking at the impact of the drug to relieve constipation tied to Parkinson's disease. More animal research recently published by Zasloff and his team found that the drug lowered toxic αS clump formation and its toxicity.
The autoimmune link
Scientists at Columbia University Medical Center (CUMC), and the La Jolla Institute for Allergy and Immunology, published a recent study that found autoimmunity — when the body’s immune system attacks the body’s own tissues — plays a role in Parkinson’s disease.
The study in Nature states that therapies to diminish the immune response could prevent neuron death and better treat the disease.
According to the research, two fragments of αS can activate the T cells involved in autoimmune attacks.
The buildup of damaged αS can trick T cells into thinking dopamine neurons are foreign, which launches immune system responses by both helper and killer T cells.
The αS proteins are misprocessed in virtually all Parkinson’s patients, David Sulzer, PhD, a study co-leader and a professor of neurobiology at CUMC, told Healthline.
Evaluating immune activity
For their study, the researchers as CUMC and the La Jolla Institute for Allergy and Immunology, analyzed αS in blood samples taken from 67 people with Parkinson's disease and a control group of 36 age-matched people without Alzheimer’s.
The researchers didn’t see a lot of immune cell activity in the control group’s samples, but the samples from the people with Alzheimer’s had a lot. The immune response was also tied to a gene variant in the immune system that many people with Alzheimer’s carry.
Sulzer believes that autoimmunity in Parkinson's disease arises when neurons can’t get rid of abnormal αS.
However, researchers don’t know if the immune system’s response to αS is the initial cause of Parkinson’s, or if it contributes to neuronal death and worsening symptoms.
“If abnormal αS begins to accumulate, and the immune system hasn't seen it before, the protein could be mistaken as a pathogen that needs to be attacked,” Sulzer said in a statement.
Taking an immunotherapy approach that could boost the immune system’s tolerance to αS may improve outlooks or prevent symptoms from getting worse in people with Alzheimer’s.
These findings could pave the way for a better diagnostic test that would pinpoint who is at risk or in early disease stages, said Alessandro Sette, a professor at the Center for Infectious Disease at La Jolla Institute for Allergy and Immunology.