Researchers at Johns Hopkins have identified a biological process that appears to trigger a particular form of Parkinson's disease present in a large number of patients. The researchers worked with human neurons and fruit flies.
A report on the study, in the April 10 issue of the journal Cell, could lead to new treatments for this disorder.
"Drugs such as L-dopa can, for a time, manage symptoms of Parkinson's disease, but as the disease worsens, tremors give way to immobility and, in some cases, to dementia. Even with good treatment, the disease marches on," says Ted Dawson, M.D., Ph.D., professor of neurology and director of the Johns Hopkins Institute for Cell Engineering,
Over the years, it was found that blocking kinase activity in mutated LRRK2 halted degeneration, while enhancing it made things worse. But nobody knew what proteins LRRK2 was acting on.
"For nearly a decade, scientists have been trying to figure out how mutations in LRRK2 cause Parkinson's disease," said Margaret Sutherland, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke. "This study represents a clear link between LRRK2 and a pathogenic mechanism linked to Parkinson's disease."
Dawson went fishing for the right proteins using LRRK2 as bait. When his team began to identify those proteins, Dawson says they were surprised to discover that many were linked to the cellular machinery, like ribosomes, that make proteins. Nobody, says Dawson, suspected that LRRK2 might be involved at such a basic level as protein manufacture.
Unsure if they were right, the team then tested the proteins they identified to see which of them, if any, LRRK2 could add phosphate groups to. They came up with three ribosomal protein candidates — s11, s15 and s27. They then altered each ribosomal protein to see what would happen. It turned out that mutating s15 in a manner that blocked LRRK2 phosphorylation protected nerve cells taken from rats, humans and fruit flies from death. In other words, s15 appeared to be the much sought-after target of LRRK2, Dawson says.
"When you go fishing, you want to catch fish. We just happened to catch a big one," Dawson says.
With the protein now identified, Dawson's team is tackling further experiments to find out how excess protein production causes dopamine neurons to degenerate. And they want to see what happens when they block LRRK2 from phosphorylating the s15 protein in mice, to build on their findings from fruit flies and nerve cells grown in a dish.
"There's a big chasm between animal disease models and human treatments," says Ian Martin, Ph.D., a neuroscientist in Dawson's lab and the lead author on the paper. "But it's exciting. I think it definitely could turn into something real, hopefully in my lifetime."