Working with human neurons and fruit flies, researchers were able to identify and then shut down a biological process that seemed to trigger a particular form of Parkinson's disease present in a large number of patients.
Ted Dawson, M.D., Ph.D., professor of neurology and director of the Johns Hopkins Institute for Cell Engineering, said drugs like 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.
Further evidence for a role of genetics in Parkinson's disease appeared a decade ago when researchers identified key mutations in an enzyme known as leucine-rich repeat kinase 2, or LRRK2 - pronounced "lark2." When that enzyme was cloned, Dawson, together with his wife and longtime collaborator Valina Dawson, Ph.D., professor of neurology and member of the Institute for Cell Engineering, discovered that LRRK2 was a kinase, a type of enzyme that transfers phosphate groups to proteins and turns proteins on or off to change their activity.
Over the years, it was found that blocking kinase activity in mutated LRRK2 halted degeneration, while enhancing it made things worse.
When Dawson's 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.
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.
The study has been published in the journal Cell.
