Researchers at Johns Hopkins' Institute for Cell Engineering (ICE) have discovered a protein that could be the best new target in the fight against Parkinson's disease since the brain-damaging condition was first tied to loss of the brain chemical dopamine.
Over the past year, the gene for this protein, called LRRK2 (pronounced "lark-2"), had emerged as perhaps the most common genetic cause of both familial and unpredictable cases of Parkinson's disease. Until now, however, no one knew for sure what the LRRK2 protein did in brain cells or whether interfering with it would be possible.
Now, after studying the protein in the lab, Johns Hopkins researchers report that the huge LRRK2 protein is part of a class of proteins called kinases and, like other members of the family, helps control other proteins' activities by transferring small groups called phosphates onto them. The researchers also report that two of the known Parkinson's-linked mutations in the LRRK2 gene increase the protein's phosphate-adding activity. The findings appear in the current (Nov. 15) issue of the Proceedings of the National Academy of Sciences.
"We know that small molecules can interfere with this kind of activity, so LRRK2 is an obvious target for drug development," says Ted Dawson, M.D., Ph.D., co-director of the Neural Regeneration and Repair Program within ICE and a leader of the study. "This discovery is going to have a major impact on the field. It's going to get people talking about kinase activity."
Because kinases affect a number of other proteins, LRRK2's link to Parkinson's may be a result of either its own activity or a shift in the activities of one or more "downstream" proteins.
"The next step is to prove that LRRK2 overactivity results in the death of brain cells that produce dopamine, the defining pathology of Parkinson's disease, and to figure out how it does so," says Dawson, who cautions that the large size of the LRRK2 gene and protein could make clinical application of the Hopkins discovery years away.
"For example, we would want to isolate the active part of the LRRK2 protein and use that more manageable part to screen for molecules that would block its activity. But what takes us a second to think of could take four or five months to do," says Dawson. "These things may not come as fast as the field wants."
The LRRK2 protein, sometimes called dardarin, is 2,527 building blocks long. In contrast, the alpha-synuclein protein, the first to be linked to Parkinson's disease, is only 140 building blocks long. The parkin protein, linked to more cases of familial Parkinson's disease than any other to date (although LRRK2 is likely to break that record), is considered "big" at 465 building blocks long.
Undaunted by the size of the LRRK2 gene and protein, Andrew West, Ph.D., a postdoctoral fellow and co-first author of the paper, spent months extracting the full-length gene from human brain samples and developing reliable experiments to test how mutations affected LRRK2's activity. Co-first author Darren Moore, Ph.D., also a postdoctoral fellow, built the tools to get bacteria to make mounds of LRRK2 protein and two mutant versions and also tracked down the LRRK2 protein's location inside cells.
The research team's experiments showed that the LRRK2 protein, in addition to its role as a kinase, actually sits on mitochondria, cells' energy-producing factories, where it likely interacts with a complex of proteins whose failure has also been implicated in Parkinson's disease.
Mutations in LRRK2 were first tied to Parkinson's disease in 2004 and to date explain perhaps 5 percent to 6 percent of familial Parkinson's disease (specifically so-called autosomal dominant cases, in which inheriting a single faulty copy of the gene results in disease) and roughly 1 percent of Parkinson's disease in which there is no family history. But few of the gene's genetic regions have been analyzed in depth.
"As researchers comb through the rest of the LRRK2 gene, it seems likely that more mutations will be found and that it will be tied to more varieties of the disease," says Dawson. What's known about LRRK2 so far suggests that it might connect diseases long thought to be distinct, particularly Parkinson's disease and conditions known as "diffuse Lewy body disease," named for the bundles of certain proteins that build up inside cells in the brain in affected people. As a result, studying LRRK2 might improve understanding of and eventually treatment for more than just Parkinson's disease itself, Dawson says.
The research was funded by the National Institute of Neurological Disorders and Stroke, the Lee Martin Trust, the Sylvia Nachlas Trust, the National Parkinson Foundation and the American Parkinson's Disease Association.
Authors on the paper are Andrew West, Darren Moore, Saskia Biskup, Artem Bugayenko, Wanli Smith, Christopher Ross, Valina Dawson and Ted Dawson, all of Johns Hopkins. Valina Dawson is co-director of the Program in Neuroregeneration and Repair of the Institute for Cell Engineering at Johns Hopkins.
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