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March 1, 2005 -- No. 77
UNC findings may help explain cause
of most common movement disorder
By STUART SHUMWAY
UNC School of Medicine
CHAPEL HILL -- Scientists at the University of North Carolina at Chapel Hill may have identified the genetic basis underlying essential tremor disease, the most common human movement disorder.
The discovery comes from studies involving a strain of genetically altered mice that show the same types of tremor and similar lack of coordination as people affected by essential tremor.
This animal model of the disease might prove useful for screening potential treatments, said Dr. A. Leslie Morrow, associate director of UNC’s Bowles Center for Alcohol Studies and professor of psychiatry and pharmacology in UNC’s School of Medicine.
"We believe that these mice could explain one etiology, or origin, of essential tremor disease in humans because of the marked similarities between the mouse model and the human disease," said Morrow, who led the study team.
A report of the findings will appear in the March issue of the Journal of Clinical Investigation.
An estimated 5 million Americans are affected by essential tremor, a neurological disease characterized by an uncontrollable shaking of the limbs, in particular the arms and head. Unlike resting tremor associated with Parkinson’s disease, symptoms of essential tremor are noticeable during movement, such as lifting a cup of coffee.
The causes of essential tremor disease remain unknown, and current therapies are either partially effective or carry undesirable side effects.
The finding is serendipitous, Morrow said, because the study was initiated in an effort to learn more about alcoholism and the tremors that result from alcohol withdrawal. Her group had been examining a unique breed of laboratory mice that has been genetically engineered to lack a molecule called the gamma-aminobutyric acid-A (GABA-A) receptor alpha-1 subunit.
GABA-A receptors reside on the surface of brain cells where they help the brain to relay "stop" messages throughout the body. Two alpha-1 subunits combine with three other proteins to form the most common type of GABA-A receptor, but this subunit is absolutely required for these GABA-A receptors to exist in brain, Morrow said.
The mice lacking alpha-1 subunits have about 50 percent fewer GABA-A receptors in the brain than normal mice. A defect in GABA-A receptor function could contribute to the loss of muscle control that characterizes essential tremor patients, Morrow said.
"There is a reduction of the GABA-A receptor alpha-1 subunit in animal models of alcohol dependence, so we wanted to study the mice. As soon as we obtained them we noticed that they had a tremor."
The symptoms in GABA-A receptor alpha-1 deficient mice had the same properties as those in people who suffer from essential tremor, suggesting to the authors that the mice might respond to drugs used to treat human patients.
"Very low doses of alcohol are effective at ameliorating tremor in human patients. Interestingly, we observed the same effect in these mice – they are exquisitely sensitive to alcohol," said Morrow.
Additional compounds that ease the symptoms of essential tremor in humans, such as the anticonvulsant primidone and the beta-blocker propranolol, also had partial alleviating effects in the mutant mice.
"The work by the Morrow group clearly implicates the GABA system in human essential tremor," said Dr. Kirk Wilhelmsen, associate professor of genetics and neurology at UNC. "These mice provide a framework for further pharmacologic study of essential tremor and currently are the best available model for the condition."
Future studies will examine essential tremor patients for polymorphisms or variations in the DNA sequence that might adversely affect GABA-A receptors.
"This is one example of how animal research can lead to progress in understanding and treating human disease," said Morrow.
In addition to Morrow, co-authors from the Bowles Center for Alcohol Studies include Dr. Jason E. Kralic, Dr. Hugh E. Criswell, Jessica Osterman, Todd K. O’Buckley, Mary-Beth E. Wilkie and Dr. George R. Breese. Other co-authors include Dr. Douglas B. Matthews from the University of Memphis’ department of psychology and Dr. Kristin Hamre from the University of Tennessee’s department of anatomy and neurobiology.
The GABA-A receptor alpha-1 deficient mice were engineered and generated by collaborator Dr. Gregg E. Homanics of the University of Pittsburgh, also a co-author in the study.
The work was funded by grants from the National Institutes of Health, including the National Institute on Alcohol Abuse and Alcoholism.
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School of Medicine contact: Les Lang, (919) 843-9687 or firstname.lastname@example.org