Researchers long ago identified a molecule that they felt held the secrets to a treatment for Parkinson’s disease, but the tiny protein known as Nurr1 had a complex lock that no one has been able to crack for more than a decade.
On Thursday, a team at the University of California, San Francisco, reported that they have photographs that show a way inside Nurr1 and a place where drugmakers could launch an assault on Parkinson’s. Their research is ongoing, but the latest findings appeared in Cell Chemical Biology.
“This molecule is widely regarded as an outstanding target for developing therapeutics to treat Parkinson’s disease,” said Pamela England, an associate professor of pharmaceutical chemistry in UCSF’s School of Pharmacy. “It’s a lot of years that people have wanted to pursue this target and haven’t had the structure, atomic resolution structure...to help them do it.”
Parkinson’s disease, like Alzheimer’s, ALS and Huntington’s disease, is a progressively debilitating illnesses with no cure. People who have the condition find it difficult to control moods and muscles because neurons in the midbrain can’t access enough of a key chemical known as dopamine that transmits signals between brain cells.
No one knows why this phenomenon occurs, but it affects 10 million people around the world.
Existing drugs provide only a temporary boost to dopamine signaling, but UCSF researchers said they believe they’ve identified a keyhole on Nurr1. That keyhole, they said in their paper, is located where another atom binds to a pocket on Nurr1. To find that pocket, researchers at UCSF had to figure out how to crystallize the Nurr1 molecule, locate atoms attached to it and create a high-resolution picture of a site where another atom had attached itself.
That work began in 2015, and after 18 months, researchers had enough information to start testing out their hypotheses and writing the paper on their discoveries. England said that her team found that the DHL molecule is too unstable and reactive to be of much use in the therapeutic process but that drugmakers will likely try to develop other compounds that will bind to the site.
England said the molecule photographed on Nurr1 is a substance produced when cells dispose of excess dopamine. She and other researchers did further experiment on the substance, known as DHI, in laboratories and on zebrafish. They found that it increased Nurr1 activity, stimulating the genes involved in storing and producing dopamine.
That is exactly what pharmacologists have hoped to achieve with a Nurr1-targeting drug, England said.
“We hope these insights will lead to drugs that for the first time can target the underlying causes of Parkinson’s disease,” England said. “But more immediately, this discovery will allow us to better understand Nurr1’s role in the earliest stages of the disease. As always, with understanding comes hope.”
It typically takes 10 to 15 years to develop new drug therapies, England said, but the U.S. Food and Drug Administration could choose to fast-track therapies that drugmakers can show would not cause harm in trials.
“If you’re not going to do any harm, is there a chance you’re going to do some good?” England asked. “It all depends on the disease and how many people are impacted.”
What: Want to learn more about the latest advances in Parkinson’s research? The Parkinson’s Foundation is hosting a free educational event called “New Frontiers in Parkinson’s Research and Care.”
When: March 16, 9 a.m. to 1 p.m.
Where: Mission Oaks Community Center. 4701 Gibbons Drive, in Carmichael