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New Drug Target Studied for Parkinsonís Disease

In early studies, scientists have discovered that blocking an enzyme called LRRK2 can protect brain cells from the damage that occurs in Parkinson’s disease (PD).  The report appeared in the August 22, 2010 issue of Nature Medicine.

 Although it is unusual for Parkinson’s to be caused by a genetic mutation, LRRK2 is one of about a dozen genes researchers have discovered that — when mutated — cause or contribute strongly to PD.  About two percent of people living with PD carry a mutation in the LRRK2 gene.  When this occurs, their cells produce an overactive form of the LRRK2 enzyme.  This, in turn, contributes to the death of brain cells that occurs in PD, although researchers do not yet understand the mechanism.

 The new study, performed in the laboratory of Ted M. Dawson, M.D., Ph.D., at the Johns Hopkins University School of Medicine, tested whether blocking the action of the LRRK2 enzyme would prevent brain cells from dying.  The researchers first did test-tube experiments to screen chemical compounds known to inhibit the kind of reactions that LRRK2 enzymes carry out.  Of 70 compounds investigated, they found eight that worked.  Among these, three had been shown by other investigators to cross the blood-brain barrier, which is essential for any drug to be effective in brain diseases.

 The researchers then administered these three compounds to mice injected with a virus carrying the LRRK2 mutation.  When infected by this virus, these mice make the mutant form of LRRK2, causing brain cells to die in the same area where nerve cell death occurs in people with PD.  After treating the mice for three weeks with the experimental compounds, the researchers examined the mouse brains to see if nerve cells had died.


  • Two of the compounds, known as GW5074 and indirubin-3’-monooxime, effectively blocked the action of the LRRK2 enzyme and prevented the death of mouse neurons.

What Does it Mean?

Ever since the link between a mutation in the LRRK2 gene and PD was discovered, researchers have been working on drugs to alter the function of the LRRK2 enzyme.  This study is the first to demonstrate that blocking LRRK2 may protect neurons in an animal model of PD.  This suggests that new therapies, based on compounds that inhibit LRRK2, could be developed for people with PD who carry a LRRK2 mutation.  Whether such treatments would be helpful only for those with PD and LRRK2 mutations or for all people living with PD is unknown.

Having established the potential behind a LRRK2 blocking therapy, further research will be needed to develop specific and effective blockers of LRRK2 that are also safe for people with Parkinson’s.  Likewise, to determine if these potential blockers could help other people with PD who do not have a LRRK2 mutation—the majority of all cases of PD, additional research will be required.  Any newly developed compound would then need to be tested for safety and effectiveness in clinical studies, a process that can take several years.

Reference: Lee BD, Shin JH, VanKampen J, Petrucelli L, West AB, Ko HS, Lee YI, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, Dawson TM. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nat Med. 2010 Sep;16(9):998-1000. Epub 2010 Aug 22. (

Source Date: Sep 13 2010