For release: Thursday, August 2, 2007
Lithium carbonate, a compound commonly used to treat depression, might also provide symptomatic relief for a group of inherited movement disorders that includes the fatal disease spinocerebellar ataxia type 1 (SCA1).
In Public Library of Science – Medicine (PLoS Medicine),* researchers report that they've tested lithium carbonate in mice carrying the genetic mutation that causes SCA1. The treatment reduced motor control problems, partly corrected for cognitive deficits, and appeared to slow degenerative changes in the brain, all of which are major hallmarks of SCA1 in humans.
"We used an animal model that faithfully reproduces many features of SCA1, and are hopeful that lithium will have similar benefits in people with the disease," said the study's senior author Huda Zoghbi, M.D., a professor of genetics and pediatric neurology at Baylor College of Medicine in Houston and an investigator with the Howard Hughes Medical Institute.
"We need to test the safety and benefits of lithium in a small number of patients with SCA1 before we can recommend it as a treatment," she cautioned. People taking lithium as a mood stabilizer have reported loss of coordination as a side effect – a warning that at an uncontrolled dosage, the drug could actually worsen the symptoms of SCA1. Dr. Zoghbi, whose study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), is hopeful that at the right dose, lithium could be useful against SCA1 and a broader class of genetic diseases that includes Huntington's disease.
SCA1 tends to appear around age 30. At first, it damages the cerebellum, a brain structure involved in motor control, but eventually it affects parts of the brain involved in memory, including a structure called the hippocampus. Huntington's typically has an adult onset and a progressive course. It causes involuntary movements, dementia, and dramatic personality changes. Both diseases cause breathing and swallowing problems that often prove fatal.
SCA1, Huntingon's and other diseases, sometimes called polyglutamine diseases, are caused by the genetic equivalent of a stutter – a repetitive sequence of DNA that interrupts an otherwise normal gene. The affected gene in each disease is different, with each one carrying the instructions for making a distinct protein, but at least one consequence is similar. When the gene is "read," the resulting protein ends up containing a long, repetitive sequence of its own – polyglutamine. In SCA1, the affected protein is called ataxin-1. Scientists believe that polyglutamine-containing proteins latch onto other normal proteins and interfere with their vital functions.
Dr. Zoghbi's previous work has shown that in SCA1, polyglutamine-expanded ataxin-1 alters the activity of genes in the cerebellum before symptoms of the disease appear. She chose to test lithium in mice with the disease because "we know that it affects gene expression [levels] and that, under some circumstances, it can be neuroprotective," she said.
"Polyglutamine diseases are currently untreatable, and have been the focus of intense research funded by NINDS," said Katrina Gwinn, M.D., a program director at NINDS. "This study is an excellent example of how a better understanding of disease mechanisms is leading to new treatment strategies."
Dr. Zoghbi and her team gave the mice lithium carbonate in their food, either from three weeks of age, before the first signs of disease, or at five weeks of age, after the first signs of disease. After several weeks of this treatment, the mice performed better on tests of motor coordination and memory than did untreated mice. When the researchers compared the brains of treated and untreated mice, they found that lithium partially rescued the degeneration of cells in the hippocampus.
Lithium did not improve the life span of the mice, and its effects on motor and cognitive function seemed to diminish after about 20 weeks of age. According to Dr. Zoghbi, if lithium has similar effects in people with SCA1, it could significantly enhance their quality of life.
Meanwhile, Dr. Zoghbi and others continue to investigate the possibility that lithium might have broad use against polyglutamine diseases. In a previous study, one group found that lithium improved motor performance in a mouse model of Huntington's disease. Dr. Zoghbi said she plans to test lithium in a mouse model of spinocerebellar ataxia type 7, another polyglutamine disease. She'll also continue to work with Harry Orr, Ph.D., to probe lithium's mode of action. Dr. Orr is an author on the current study and a geneticist at the University of Minnesota in Minneapolis.
*Watase K et al. "Lithium Therapy Improves Neurological Function and Hippocampal Dendritic Arborization in a Spinocerebellar Ataxia Type 1 Mouse Model." Public Library of Science – Medicine, May 2007, Vol. 4.
-By Daniel Stimson, Ph.D.
Last Modified December 16, 2015