Research Author: Weill Cornell Medical College Last Updated: Jun 8, 2009 - 
12:08:54 PM

Mice With Parkinson's Disease Gene May Point the Way to New Treatments
By Weill Cornell Medical College
Jun 8, 2009 - 12:07:14 PM

(HealthNewsDigest.com) - NEW YORK -- Scientists at Weill Cornell Medical 
College have developed a new mouse model of Parkinson's disease (PD) that 
successfully reproduces the impairments of movement and the degenerative 
brain changes that occur in the human disease. Their research, performed in 
collaboration with investigators at Columbia University Medical Center, 
appears in the June 7 issue of the journal Nature Neuroscience.

"Because this new mouse model replicates the pathogenesis of human 
Parkinson's disease so closely, it promises to be a major boon to 
Parkinson's research, both in terms of basic science and drug development," 
says Dr. M. Flint Beal, study co-author and professor of neurology and 
neuroscience at Weill Cornell Medical College. "While there are many 
treatments for the symptoms of PD, no current therapies prevent the 
inevitable progression of the disease. One reason for the inability to 
develop such therapies is that there has been no truly workable animal model 
of the human disease. This new model will now address this critical need."

Earlier attempts to create a mouse model for Parkinson's continually fell 
short due to technological limitations. Using a new transgenesis technology 
called BAC (bacterial artificial chromosome) that allows researchers to 
insert large DNA fragments into the genome, senior author Dr. Chenjian Li, 
assistant professor of neurology at Weill Cornell Medical College, and his 
colleagues were able to introduce into the mouse's genome a mutant form of 
the LRRK2 gene -- the most common genetic cause of PD.

The Weill Cornell team observed that the mice expressing the mutant form of 
the gene became very slow to move as they became older, just like human PD 
patients. Remarkably, the mice became able to move normally when treated 
with levodopa, the same drug that is commonly used to treat human patients.

Further research by Drs. Beal and Li and their labs revealed that the mice 
with impaired movement also had impaired release of the brain 
neurotransmitter dopamine, just as it occurs in the human disease. Dr. 
Robert Burke, the Alfred and Minnie Bressler Professor of Neurology (in 
Pathology) at Columbia University Medical Center, and his colleague Ms. 
Tinmarla Francis Oo, senior staff associate at Columbia University Medical 
Center, further discovered that the dopamine deficit came from 
disintegration, not of the dopamine neurons themselves, but of their axons, 
the long, filament-like structures responsible for transmitting dopamine to 
distant targets in the brain. Their insights, says Dr. Li, are helping us 
understand the disease at a deeper level -- something that will lead us to 
better treatments and possibly even a cure for Parkinson's disease.

There are currently two standard types of treatment for Parkinson's: 
medication and a surgical technique called deep brain stimulation, which 
achieves similar results for some patients. Neither approach, however, stops 
the progression of the disease as it lays waste to the brain's dopamine 
system and inexorably erodes key physical, cognitive and psychological 
functions.

0Says Dr. Li: "The new model will provide scientists with an appropriate 
'stage' on which to screen for effective medications. It will also show us 
the disease in real time, allowing us to track its progression at a cellular 
and molecular level. What we learn will then feed back into the drug 
development process.

"From a longer-term perspective, this also gives us a picture-window into 
normal biology," he continues. "The new mouse model will provide an 
opportunity to investigate the brain's dopaminergic system, a brain circuit 
critical to movement, emotions and drug addition."

The study's co-first authors were Yanping Li and Wencheng Liu of Weill 
Cornell Medical College. Additional co-authors included Kindiya Geghman and 
Yi Tang of Weill Cornell; Lei Wang and Mikhail Bogdanov of Weill Cornell and 
Bedford VA Medical Center, Bedford, Mass.; and Vernice Jackson-Lewis, Chun 
Zhou and Serge Przedborski of Columbia University Medical Center.

The study was supported by the National Institute of Neurologic Disorders 
and Stroke, the Michael J. Fox Foundation and the Parkinson's Disease 
Foundation.

Parkinson's is the second most common neurodegenerative disease after 
Alzheimer's. In its later stages, it can be extremely disabling, both 
physically and mentally. The disorder not only impairs the ability to 
initiate and sustain movement, but affects cognition and mood as well. 
Aging, genetics, and environmental toxins are the main risk factors for a 
disease whose prevalence is slated to rise dramatically as the population 
ages. About 90 percent of the time, Parkinson's is sporadic in origin, 
meaning its cause is unknown. But 10 percent of cases run in families.

For more information, please visit www.cumc.columbia.edu.

For more information, visit www.med.cornell.edu.

Rayilyn Brown
Director AZNPF
Arizona Chapter National Parkinson Foundation
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