During an asthma attack, drugs such as salbutamol can help a person breathe easy by turning on a protein receptor that triggers the opening of the lung’s airways. According to a new study, drugs targeting this receptor might have another, unrelated benefit: reducing the risk of Parkinson’s disease (Science 2017, DOI: 10.1126/science.aaf3934).
“It’s an exciting clue” that could point the way toward new treatments for the neurodegenerative disease, says Clemens Scherzer of Brigham & Women’s Hospital and Harvard Medical School, who led the research team.
The findings connect the receptor targeted by asthma drugs to the expression of the gene that encodes the protein α-synuclein. In the brains of people with Parkinson’s, this protein aggregates and forms characteristic clumps. Scientists are working on therapies to clear toxic forms of the protein from the brain. But, Scherzer says, scientists still debate which form of α-synuclein is the toxic one.
He and his colleagues decided to skip that debate. “We thought we’d leave that to smarter people to figure out,” Scherzer says. “Instead we decided to go to the source and find drugs that could reduce the expression of the α-synuclein gene.”
They screened 1,126 compounds, including drugs approved by the U.S. Food & Drug Administration, to see which molecules reduced expression of the α-synuclein gene in neuroblastoma cells. They got four hits, three of which were asthma drugs targeting the β2-adrenoreceptor (β2AR).
Experiments in mice showed that one of these drugs, clenbuterol, reduced expression of the α-synuclein gene in part of the brain affected by Parkinson’s. The drug also protected neurons typically destroyed by the disease in mice.
The team also found a connection between these drugs and Parkinson’s in people. Working with Trond Riise of the University of Bergen, the researchers analyzed medical data from 4.6 million people in Norway between 2004 and 2014. The Norwegian government maintains databases of medical records of citizens and makes them available to researchers. Through its analysis, Scherzer’s team found that people taking salbutamol had a reduced risk of developing Parkinson’s. Meanwhile, Norwegians taking the hypertension drug propranolol, which turns off β2AR, had an increased risk.
The study offers a potentially important advance toward new drug targets for Parkinson’s, says Steve Finkbeiner, director of the Taube-Koret Center for Neurodegenerative Disease Research. But, he says, the data also raise questions that require follow-up. For example, Norwegians tend to be more genetically homogeneous than other populations. So, Finkbeiner wonders how well the findings will translate to a more diverse population.
As for the asthma drugs themselves, they have known cardiovascular side effects. Further work is needed to address those issues and to confirm the molecules’ clinical benefit in actual Parkinson’s patients, says John Q. Trojanowski of the University of Pennsylvania School of Medicine. “So cautious optimism is in order,” he adds.