For release: Monday, November 29, 2010
With support from the National Institute of Neurological Disorders and Stroke (NINDS), researchers are investigating a potential new therapeutic approach to Parkinson's disease that would target a problematic gene called LRRK2.
Parkinson's disease attacks a part of the brain that controls movement, leading to involuntary shaking, slowed movement, stiffened muscles, and other symptoms that worsen over time. Mutations in the LRRK2 gene are the most common known cause of the disease. Worldwide, LRRK2 is implicated in as many as 10 percent of familial Parkinson's cases and about 4 percent cases without any family history. In people of North African descent, a single LRRK2 mutation (called G2019S) accounts for 30-40 percent of all Parkinson's cases.
The LRRK2 protein acts as a kinase, which means that it plays a key role in controlling the movements and functions of other proteins within the body’s cells. Most of the known mutations in LRRK2 appear to boost its kinase activity. These properties make LRRK2 "a solid drug target," said Ted Dawson, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University in Baltimore. Dr. Dawson is also director of the Morris K. Udall Parkinson's Disease Research Center of Excellence at Hopkins.
Because kinases are implicated in ailments from cancer to heart disease, scientists have invested heavily in efforts to understand how they work and how to control them pharmacologically, according to Dr. Dawson. That has led to the development of dozens of kinase inhibitors.
Recently, Dr. Dawson led a team that tested a broad spectrum of 70 kinase inhibitors for their effects against LRRK2. The team found that several organic compounds called indolinones were the most effective at tamping down LRRK2's kinase activity.
The researchers went on to test two of the indolinone compounds in a cell model of LRRK2-linked Parkinson's disease. In this model, the G2019S mutation found in some patients with Parkinson's disease is introduced into rat neurons grown in culture. Normal neurons growing in culture connect to each other via extensions called neurites. Cells carrying the G2019S mutation retract their neurites and die. However, treatment with the indolinone compounds protected the cells against injury and death.
Next, the researchers tested the indolinones in a mouse model of LRRK2-linked Parkinson's disease. In this model, a virus carrying a mutant version LRRK2 gene is injected into the mouse brain near the substantia nigra, the brain region most severely affected by Parkinson's. The virus ferries the gene to cells within the substantia nigra, causing widespread cell death by three weeks after injection. The researchers found that twice-daily injections of the indolinones reduced the cell death caused by LRRK2.
Those findings were published in Nature Medicine.* The researchers have since used medicinal chemistry to generate more potent LRRK2 inhibitors, which they plan to test in mice and eventually in monkeys.
"We are keen to see if we can extrapolate our findings to an animal where behavior, neurochemistry, imaging and other clinical assessments are possible," said Howard Federoff, M.D., Ph.D., a professor of neuroscience, Executive Vice President for Health Sciences and Executive Dean of the School of Medicine at Georgetown University in Washington, D.C.
Dr. Federoff developed the viral system for delivering mutant LRRK2 to the mouse brain. He is currently leading an effort to adapt the system for use in monkeys.
The research described in Nature Medicine was supported by NINDS, the National Institute of Environmental Health Sciences (NIEHS), the Army Medical Research and Material Command, the Mayo Foundation and the Michael J. Fox Foundation. Research to develop a monkey model of LRRK2-linked Parkinson's disease is supported by a Grand Opportunities (GO) grant from NINDS, funded through the American Recovery and Reinvestment Act (ARRA). For more information about research funded by NINDS and ARRA, please visit NINDS Recovery Act Stories.
- By Daniel Stimson, Ph.D.
Lee, B.D. et al. "Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease." Nature Medicine, Vol. 16(9), pp. 998-1000, September 2010.
The mouse substantia nigra (yellow) is lit up by a fluorescent protein delivered using a virus. Reprinted from B.D. Lee et al., Nature Medicine, September 2010
Last Modified February 9, 2011