Progress in treating Parkinson’s disease—a progressive neurological illness that causes tremors, muscle rigidity, and dementia—has been painfully slow, in large part because scientists still don’t fully understand the molecular events that kill select brain cells. What they do know is Parkinson’s leaves behind a telltale mark: clumps of the misfolded alpha synuclein (αS) protein in the brains and guts of patients at autopsy. In its normal form, the protein is widely thought to help brain cells communicate, but researchers have now uncovered another role—αS plays an essential part in immune and inflammatory responses in the gut.
The new work is “extremely well done and very exciting,” says physician-scientist Michael Schlossmacher, who studies Parkinson’s disease at the Ottawa Hospital Research Institute but was not involved with the study. He adds that the protein’s “pivotal role” in immunity may help explain why chronic infection or inflammation can lead to a higher risk of Parkinson’s.
Others in the field, however, question the work’s relevance to the brain disorder. The dominant view among researchers is that misfolded αS aggregates and takes on new toxic properties, and some say the natural role of the protein, although interesting, may be irrelevant to pursuing needed treatments.
Parkinson’s disease, the second most common neurodegenerative ailment after Alzheimer’s, affects one in 331, or about 1 million, people in the United States and at least 7 million people globally. Many patients are diagnosed in their 60s, as brain cells that make the neurotransmitter dopamine die and lead to symptoms. But the disease can also strike the young—including those who produce too much αS, or fail to break it down—because of rare genetic mutations. Other risk factors include sex—prevalence is 40% to 50% higher in men than in women—and some chronic inflammatory diseases, such as inflammatory bowel disease and chronic hepatitis C. Oral dopamine can mitigate symptoms, but the 60-year-old treatment isn’t a cure and ultimately fails to prevent worsening symptoms and death.
But some scientists are increasingly convinced that αS’s normal functions may play a role in causing the disease, and need to be clearly defined to make progress. Abundant inside brain cells, αS is thought to be central to the functioning of synapses, the communication junctions between neurons. But its exact role at these sites has largely remained a mystery. “We are terrible at treating Parkinson’s,” says David Beckham a neurovirologist at the University of Colorado School of Medicine. “Because we just have no clue what this protein is doing.”
Recent work has started to suggest another role—in immunity. In 2016, Beckham and colleagues discovered neurons in people and mice whose brains were infected by West Nile virus made αS in response. In mice genetically engineered to lack αS, the severity of the brain infection and the mortality of the disease were far worse. And a 2017 study found that, in children with gastrointestinal inflammation and intestinal transplant recipients infected with norovirus, nerve endings in the inflamed walls of the upper intestine secreted αS. The more inflammation, the more αS was made. Crucially, that study demonstrated that the released αS attracted inflammatory cells and stimulated the maturation of dendritic cells, key defenders that present bits of foreign pathogens to white blood cells, kicking off an immune response.
To find out whether αS was simply an extra at the scene or was necessary to trigger the immune response, the same researchers from the 2017 study injected compounds from bacteria into the abdominal cavities of two groups of mice: those genetically engineered to lack αS and those capable of making the protein. In the regular mice, nerve endings in the large intestine and diaphragm began to pump out αS just hours after injection, powerfully attracting and activating immune cells, the researchers wrote yesterday in Cell Reports.
Concentrations of αS were higher in the diaphragm, which was nearer the injection site. But its production also occurred “millions of miles away,” in the nerve cells of the colon, says co-author Denise Barbut, a neurologist and co-founder of Enterin, a biotechnology company developing treatments for neurodegenerative diseases including Parkinson’s.
Mice engineered to lack αS had limited, late responses. Notably, further experiments revealed abdominal white blood cells, which are also capable of making αS, were making very little of the protein. That suggests it is nerve cells—not immune cells—that are kick-starting the inflammatory response, says co-author Michael Zasloff, a professor of surgery and pediatrics who is scientific director of the MedStar Georgetown Transplant Institute.
“[This] argues that alpha synuclein is really pivotal and centrally involved in the immune response,” adds Joost Oppenheim, an immunologist at the National Cancer Institute and the senior author of the paper.
Barbut suspects αS’s immune triggering isn’t confined to the abdomen. “Our guess is that there is massive induction of alpha synuclein everywhere, both in the periphery and in the brain, alarming the entire nervous system of the existence of a threat at a specific [peripheral] site.” But she concedes the team didn’t look at the mice’s brains, which she calls the “big next step.”
Some researchers are pointedly skeptical because of this missing piece. Examining the mice’s brainstems would be essential to identifying the signature pathology of Parkinson’s—the loss of dopamine-producing neurons there. “All the studies they have performed have nothing to do with Parkinson’s disease,” says Aletta Kraneveld, a pharmaco-immunologist who studies gut-brain connections at Utrecht University. “The link is in my opinion a bit far-fetched.”
Malú Gámez Tansey, a neuroscientist at the University of Florida, agrees. “The real $64 million question, the missing link, is: ‘What happens mechanistically to the alpha synuclein that changes it from a protein that is just serving its normal function to a pathogenic alpha synuclein that is associated with disease?’” Despite the new paper, she says “that is still a black box.”