Alpha-synuclein Plays ‘Critical’ Role in Immune Responses to Inflammation

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The protein alpha-synuclein, which has a well-established role in the development of Parkinson’s disease, is necessary for the body to mount a normal immune response against infections.

“This study provides further evidence that αS [alpha-synuclein], the protein intimately linked with the pathogenesis of PD [Parkinson’s disease], is a critical component of the mammalian immune system,” its researchers wrote, adding that its findings might also support the role of a gut-brain axis in the disease.

Their study “Alpha synuclein, the culprit in Parkinson disease, is required for normal immune function,” was published in Cell Reports.

At the cellular level, one of the hallmark features of Parkinson’s is the buildup of aggregates, or clumps, of alpha-synuclein protein in nerve cells. These protein aggregates are thought to be toxic to the cells and contribute to brain cell death.

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While the role of alpha-synuclein in Parkinson’s has been clearly established, not much is known about this protein’s normal function. In the past few years, some studies have suggested that the alpha-synuclein protein may be needed for the proper workings of the immune system.

A team of scientists at the National Institutes of Health (NIH) and Enterin, a company working in neurodegenerative diseases, sought to further explore this protein’s role by conducting a series of experiments in mice. The researchers used two mouse strains — one that had been engineered so the mice did not produce alpha-synuclein, and a normal or wild-type strain for reference.

In initial experiments, peptidoglycan — a molecule found in many infectious bacteria — was injected into the mice’s abdomens. In wild-type mice this triggered a powerful inflammatory response, as evidenced by higher numbers of immune cells and pro-inflammatory signaling molecules in the injected tissue. In mice lacking alpha-synuclein, however, this inflammatory response was significantly dampened.

“These studies demonstrate that endogenous [alpha-synuclein] plays a role in the early stages of an inflammatory response to an inflammatory stimulus,” the researchers wrote.

Further experiments showed that levels of alpha-synuclein in healthy mice rose shortly after bacterial peptidoglycan was injected, suggesting that this protein was being released in response to the inflammatory stimulus.

The researchers then conducted a battery of tests on different mice tissues, looking for the source of alpha-synuclein release due to inflammation. Results showed that the most likely source of alpha-synuclein during inflammation was neurons, a type of nerve cell found in the brain and spinal cord (the central nervous system).

Additional cell experiments demonstrated that treatment with alpha-synuclein could promote a more pro-inflammatory state in certain immune cells, such as macrophages and dendritic cells. Similar findings were demonstrated in mice: injecting mice with alpha-synuclein promoted immune cell recruitment and other pro-inflammatory processes.

Collectively, these finding suggest that alpha-synuclein normally functions as an alarmin. As the name implies, an alarmin is a signaling protein released early in the process of inflammation to essentially “sound the alarm” that something is wrong, and to trigger the activation of the immune system.

“Alarmins are endogenous proteins that both alert and direct the immune system to effectively tackle an infectious insult. [Alpha-synuclein] appears to be an alarmin,” Joost Oppenheim, MD, PhD, a study co-author with the NIH’s National Cancer Institute, said in a press release.

In a final set of experiments, the team tested whether mice lacking alpha-synuclein were able to mount an antigen-specific immune response — the kind of immune response that recognizes a specific infectious invader. Results indicated that, without alpha-synuclein, significantly fewer immune cells are recruited to participate in this type of immune response, ultimately reducing the potency of the response.

Alpha-synuclein secretion, the researchers concluded, “is critical for the generation of antigen-specific immune responses.” It acts as “a critical alarmin signal to amplify innate/inflammatory and antigen-specific immune responses.”

They also noted that this work might support the role gut-brain axis in this disease via the enteric nervous system — the local network of nerves that innervate the gastrointestinal (GI) tract.

Previous studies have suggested that “aggregates of [alpha-synuclein] will gradually traffic from the enteric nerves to the brain leading to the subsequent clinical and pathological features” of Parkinson’s, the researchers wrote.

Chronic GI infection, like inflammatory bowel disease, is also being seen to possibly increase a person’s risk of Parkinson’s, the team added, and this study’s findings help to “explain why [alpha-synuclein] is induced in the enteric nervous system in settings such as GI infection.”

Denise Barbut, MD, a study co-author and chief medical officer of Enterin, added: “What’s remarkable is the rapid induction of [alpha-synuclein] in nerves at great distances from the site of the infectious stimulus.”

The researchers noted a need for further research into how this finding may connect to alpha-synuclein’s role in Parkinson’s.

It’s conceivable, Barbut added, “that [alpha-synuclein] production within the brain in Parkinson’s disease is triggered indirectly by a neural signal emanating from the site of a remote infection rather than being physically transported from the periphery.”

This study was funded by the NIH.