Study suggests that Parkinson's could be an autoimmune disease
For degenerative diseases like Parkinson's, any insights we can gain into its development in the brain could be vitally important in coming up new ways to apply the brakes. For this reason, a new study led by scientists at Columbia University Medical Center (CUMC) could form a key piece of the puzzle. They have found the first direct evidence that autoimmunity contributes to Parkinson's disease, by extension raising the prospect of manipulating the body's immune system to slow or even halt its progress.
Autoimmunity is the driving force behind diseases such rheumatoid arthritis and multiple sclerosis. Normally our body's immune system acts as its protector, tracking down and fighting off foreign invaders like viruses, bacteria or cancer cells. But sometimes the immune system can mistake our own cells for hostile ones, launching an attack on our healthy tissues and organs.
It was believed that dopamine neurons, whose death or impairment plays a central role in Parkinson's, were not vulnerable to such autoimmune attacks. But in 2014, David Sulzer, professor of neurobiology at CUMC found that they could. That study proposed the idea that these neurons actually were susceptible, because of proteins that form on the cell surface that serve as a green light for the immune system to recognize and attack foreign invaders.
Now in a follow-up study, Sulzer and his team have zeroed in on the mechanism behind this high-stakes case of mistaken identity, a damaged protein that accumulates in the brain cells of Parkinson's patients called alpha-synuclein. The team examined blood samples from 67 Parkinson's disease patients and 36 healthy controls after exposing them to fragments of damaged alpha-synuclein, along with other proteins found in the neurons.
This exercise allowed them to see which, if any, of the protein fragments triggered an immune response. They saw little activity in the blood samples in the healthy patients, but the T cells in Parkinson's patients, which are key players in our immune response, kicked into gear and launched a strong attack on the damaged alpha-synuclein.
"The idea that a malfunctioning immune system contributes to Parkinson's dates back almost 100 years," says Sulzer. "But until now, no one has been able to connect the dots. Our findings show that two fragments of alpha-synuclein, a protein that accumulates in the brain cells of people with Parkinson's, can activate the T cells involved in autoimmune attacks."
"It remains to be seen whether the immune response to alpha-synuclein is an initial cause of Parkinson's or if it contributes to neuronal death and worsening symptoms after the onset of the disease," said study co-leader Alessandro Sette, professor in the Center for Infectious Disease at La Jolla Institute for Allergy and Immunology. "These findings, however, could provide a much-needed diagnostic test for Parkinson's disease and could help us to identify individuals at risk or in the early stages of the disease."
There are still plenty of questions about how exactly this autoimmune response plays out, and whether or not it is an initial cause of Parkinson's or just worsens it after it sets in, but the researchers have some ideas about what could trigger it. Sulzer says that one possibility is that autoimmunity is triggered when the neurons are unable to continue getting rid of the damaged alpha-synuclein on their own.
"Young, healthy cells break down and recycle old or damaged proteins," he said. "But that recycling process declines with age and with certain diseases, including Parkinson's. If abnormal alpha-synuclein 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."
The team is now analyzing this process in more patients, and working with animal and cellular models to identify the molecular steps that lead up to it.
"Our findings raise the possibility that an immunotherapy approach could be used to increase the immune system's tolerance for alpha-synuclein, which could help to ameliorate or prevent worsening symptoms in Parkinson's disease patients," says Sette.
The research was published in the journal Nature.