Lithium improves function in mice with form of ataxia
By Ruth SoRelle, M.P.H.
Nearly 15 years ago, Huda Y. Zoghbi, M.D., professor of molecular and human genetics, pediatrics and neurology at Baylor College of Medicine, and her colleagues found the gene for a neurodegenerative disease called spinocerebellar ataxia type 1 (SCA1).
In the ensuing years, Zoghbi found other genes, but she kept chipping away at the problem presented by this devastating ataxia with symptoms that show up usually in adulthood. She and her lab developed a mouse model of the disease. They discovered the molecular changes involved at the level of the cell.
Recently, they found that an old drug – lithium – could improve the symptoms of the disorder in the mice. They reported the information in a recent issue of the journal Public Library of Science Medicine.
Lab work ready for translation
"This did not cure them," said Zoghbi, who is also a Howard Hughes Medical Institute investigator and the senior author on this paper. "It improves the symptoms, but we do not know how it will affect the disease long-term."
She warns that the drug needs further testing before it can be considered for treatment in people with spinocerebellar ataxia 1.
"It needs to be tested first in a few patients to see if they tolerate it," she said. Lithium is best known as a treatment for people with bipolar disorders, which involves wide swings in mood. If it is safe, larger studies can be undertaken.
"The polyglutamine disorders, including SCA1, have been the focus of extraordinarily creative and productive laboratory-based science," said Katerina Gwinn, director of the extramural research program of the National Institute of Neurological Diseases and Stroke. "The field is primed for translation into clinical efforts, and this possibility of a Phase I study in lithium, based on Dr. Zoghbi's work, is an extremely exciting step toward finding therapeutics to help people with these currently untreatable disorders."
Fatal disease gradually kills neurons
"This work shows the importance of discovering a gene mutation, developing a good animal model of the disease that allows you to see the molecular changes that occur and then asking if we can alter those changes in a positive way," said Zoghbi.
Zoghbi's work with spinocerebellar ataxia type 1 started with the families that had the fatal inherited disorder that gradually kills neurons, reducing the patients' ability to walk, talk, swallow and eventually breathe. She and her collaborator, Harry T. Orr, Ph.D., of the University of Minnesota in Minneapolis, eventually discovered the gene that caused SCA1 and the defective protein, ataxin 1, associated with the disorder.
Lithium studied because of known effects on neurons, genes
A defective SCA1 gene has an abnormally long stretch of DNA that repeats three nucleotides or chemicals that tell the cell to make an amino acid called glutamine. This results in the build-up of death-dealing lumps of ataxin 1 in the nuclei of neurons. It is believed that mutant ataxin 1 block the actions of other proteins called transcription factors critical to normal cell function.
Many neurons make ataxin 1, including cells that coordinate movement. Zoghbi and her colleagues chose to test lithium because it protects neurons and positively affects the expression of genes. The mouse in the study had one mutant gene that carried a long repeat of the three nucleotides and one normal gene. The mutation caused symptoms similar to those seen in humans.
Treated mice didn't live longer
In this test, the mice ate either regular food or food supplemented with lithium. After several weeks, tests showed that lithium, given to some before symptoms and others after, improved memory, learning and coordination in the SCA1 mice. It also reversed neuron degeneration in the hippocampal area of the brain in these animals and restored levels of messenger RNA, a key element of gene expression, in the animal's cerebella. However, the treated mice did not live longer.
Others who took part in this work include: Kei Watase, Jennifer R. Gatchel, Yaling Sun, Richard Atkinson, Ronald Richman and Chad Shaw of BCM; Hidehiro Mizusawa of the Tokyo Medical and Dental University in Tokyo; and Effat Emamian of the University of Minnesota in Minneapolis.
Funding for this project came from the National Institutes of Health, the Baylor Mental Retardation Research and Center and research funds donated in honor of Mrs. Mariona Nicolau del Tarre. The article is available at http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0040182
