A provocative new study by Harvard Medical School researchers suggests that a basic assumption about a protein involved in Parkinson’s disease may need to be revised, providing a new strategy for developing drugs to treat the neurological condition.
Clumps of the protein alpha-synuclein found in the brains of Parkinson’s patients are a hallmark of the disease, a progressive movement disorder often characterized by tremors. But it has long been thought that the healthy, natural form of the protein is an unfolded string, like a strand of spaghetti.
Now, a study published online by the journal Nature yesterday makes the case that the healthy protein comes packaged in a very different structure, a “tetramer’’ that looks something like four winding, helical-shaped staircases standing in a row. The work also suggests a new way to fight Parkinson’s – developing a drug that keeps that tetramer structure intact, since that shape does not appear to form clumps.
“It’s such a departure from what we thought as scientists’’ about this protein, said Dr. Dennis Selkoe, a professor of neurologic diseases at Harvard and Brigham and Women’s Hospital who led the work with Tim Bartels, a postdoctoral researcher.
“It’s as if someone designed elegant staircases in a mansion and put four side by side. . . . If you’re going to study a molecule in biology, you want to make sure you are studying it correctly.’’
The researchers suggest that it had long been assumed the protein was an unfolded strand because the rough methods traditionally used to study the protein perturb its natural form.
“If this result stands the test of time, which I believe it will based on the data I’ve seen, then it’s a new paradigm for interventions in Parkinson’s disease,’’ said Jeffery Kelly, professor of chemistry at the Scripps Research Institute, who was not involved in the research. “I think many drug companies will look at this carefully.’’
Dr. Dimitri Krainc, an associate professor of neurology at Massachusetts General Hospital, wrote in an e-mail that the study was likely to be provocative. It adds to the complexity of what is known about the Parkinson’s protein, he said, but many questions remain about the relevance of this healthy form of the protein to the form implicated in disease.
Selkoe said his laboratory embarked on the study when Bartels joined the lab, with an interest in taking approaches that had been used to understand the molecular basis of Alzheimer’s disease to probe Parkinson’s.
Researchers who study the alpha-synuclein protein had often used harsh methods like boiling or using detergents to prepare their samples, but Bartels instead handled it with the lab equivalent of “kid gloves,’’ Selkoe said. To the researchers’ surprise, the molecule had a very different structure than anyone expected. They examined the protein in multiple ways, including examining protein from their own red blood cells, to better understand the healthy protein.
Gregory Petsko, a professor of biochemistry and chemistry at Brandeis University, said the paper is convincing on its own, but that he finds it even more compelling because his own laboratory – which has been using a different approach to ask the same question – recently found very similar results.
Petsko, who collaborates with Selkoe on a different project, said that one afternoon when they were talking about work on Alzheimer’s disease, they accidentally discovered that they were independently finding the same surprising result in Parkinson’s.
“We were both actually very hesitant about what we had because it went against the prevailing dogma, and it was just enormously reassuring,’’ Petsko said. “I think that made both of us feel a lot better, because when you start to challenge an assumption like this, you always worry that you’re going to be fooled.’’
Much work remains to be done – including a hunt for compounds that keep the protein stable in its tetramer form, and efforts to understand better how the natural, healthy form of the protein is linked to the disease. Selkoe is also interested in exploring the possibility this could lead to a way to diagnose Parkinson’s, by sampling blood and measuring the structure of the protein.
“Nature has designed a way to keep it [alpha-synuclein] from aggregating,’’ Selkoe said. “Maybe we can mimic it and keep it that way.’’
By Carolyn Y. Johnson, The Boston Globe