Parkinson’s Might Be Driven by Autoimmune Processes, Researchers Say

Parkinson’s disease may in part be driven by autoimmune processes, according to researchers who discovered that certain immune cells react to alpha-synuclein — a protein that accumulates in the brains of Parkinson’s patients.

The findings, published in the journal Nature, raise the possibility that immunotherapy could be used to slow down disease processes in people with Parkinson’s. An immune reaction to alpha-synuclein could potentially also be used to identify people at risk of developing the disease.

“The idea that a malfunctioning immune system contributes to Parkinson’s dates back almost 100 years,” David Sulzer, PhD, a professor of neurobiology at Columbia University Medical Center and one of the study’s lead authors, said in a press release.

“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,” he said.

The study, “T cells from patients with Parkinson’s disease recognize α-synuclein peptides,” suggested that immune T-cells react to neurons in which large amounts of abnormal alpha-synuclein has piled up.

Together with colleagues at the La Jolla Institute for Allergy and Immunology, the research team took blood samples from 67 patients with Parkinson’s disease and 36 healthy controls of the same age and mixed them with fragments of alpha-synuclein and other neuronal proteins.

The idea was to observe how immune cells present in the blood would react to the protein parts. While immune cells from healthy people did not react much to the presence of the nerve cell components, T-cells in patients’ blood reacted strongly to alpha-synuclein. This indicated that they had been primed to recognize the protein.

The response could explain why genetic studies of Parkinson’s disease have repeatedly flagged a genetic region, which is responsible for the immune system’s ability to tell the body’s own structures from foreign ones found on microbes and tumors.

Sulzer’s lab had shown three years ago that dopamine neurons have proteins on their surfaces that act as flags that aid the immune system in recognizing foreign structures. They suggested in 2014 that T-cells had the potential to attack these neurons in an autoimmune process.

The new study provided evidence of how this might happen. According to Sulzer, the T-cells might start reacting to neurons when they start accumulating abnormal alpha-synuclein, mistakenly thinking they are a foreign structure.

“In most cases of Parkinson’s, dopamine neurons become filled with structures called Lewy bodies, which are primarily composed of a misfolded form of alpha-synuclein,” Sulzer said.

“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.”

But so far, researchers do not know if the immune response is what triggers Parkinson’s in the first place, or if it drives disease progression once the disease has been triggered by other factors.

“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,” said study co-leader Alessandro Sette, a professor in the Center for Infectious Disease at La Jolla.

The two research teams are now using animal and cell models to study the molecular steps of the autoimmune processes.

“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,” Sette said.