For release: Wednesday, October 19, 2005
For the first time, researchers have identified how the gene for a hereditary neurodegenerative disease called spinocerebellar ataxia type 1 (SCA1) disables an important group of neurons in the brain. The findings improve understanding of how SCA1 and related diseases develop and may lead to new ways of treating them.
The new study, led by Huda Zoghbi, M.D., of Baylor College of Medicine in Houston, shows that the gene mutation found in SCA1 increases the normal activity of the resulting protein, called ataxin-1. This effect is toxic to a group of neurons called Purkinje cells in a brain region called the cerebellum that coordinates movement. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appeared in the August 26, 2005, issue of Cell.*
SCA1, which typically starts in early adulthood and causes symptoms such as poor coordination, difficulty with walking and balance, and speech problems, is one of nine neurodegenerative diseases linked to a specific kind of mutation called a trinucleotide repeat. In these diseases, a three-base sequence in part of the genetic code -- cytosine, adenine, and guanine, or CAG -- is repeated many times. These repeated sequences result in a long string of amino acids called glutamines (the string is known as a polyglutamine) that interrupts the sequence of a normal protein. Researchers have previously suggested that these polyglutamine mutations may prevent the proteins from carrying out their normal functions, or that they may prevent them from being broken down, causing them to accumulate to toxic levels. The new study suggests a third mode of action: the polyglutamine string in the ataxin-1 protein helps it bind to and reduce the level of a protein called Gfi-1 that is essential for survival of Purkinje cells.
Previous research showed that an excess of the normal ataxin-1 protein could cause the same kind of neuron degeneration as the mutated protein. This suggested that the polyglutamine mutation was not the primary cause of cell death in SCA1. Dr. Zoghbi and her colleagues thought another part of the ataxin-1 protein might be key to its toxic effects. They focused on a part of the protein called the AXH domain.
The researchers studied how ataxin-1 interacts with other proteins in yeast, in flies, and in mice. They found that the fly version of the ataxin-1 gene and the human version had similar effects when they were expressed in flies. They also found that the AXH domain of ataxin-1 interacts with and decreases the level of the Gfi-1 protein and its fly counterpart, called Senseless. Both the normal and the mutated versions of human ataxin-1 reduced Gfi-1 levels in Purkinje cells. The researchers also showed that loss of Gfi-1 alone caused SCA1-like loss of Purkinje cells. This suggests that ataxin-1's effects on Gfi-1 are one of the main causes of neurodegeneration in SCA1.
In adult animals, the Gfi-1 protein and ataxin-1 are primarily found in Purkinje cells. This may explain why the Purkinje cells are particularly susceptible to death in SCA1.
The polyglutamine string found in the mutated ataxin-1 protein seems to amplify ataxin-1’s effects on Gfi-1, the researchers showed. While they are not yet sure how this occurs, the mutation may prevent cells from breaking ataxin-1 down properly, Dr. Zoghbi says. The mutation also might change the shape of the protein in a way that makes it bind to proteins like Gfi-1 longer than normal. "If you put the normal protein without the expansion into the cells, you get the same effect," she adds. "It just takes a lot more of the normal protein to cause disease."
"This tells us what area to focus on," says Dr. Zoghbi. "We can now go back and identify how this [AXH] part of the protein interacts with other proteins." The finding also may help researchers understand what goes wrong in other polyglutamine disorders, including Huntington's disease and Machado-Joseph disease.
The findings complement several other recent studies showing that normal proteins can cause neurodegenerative disease if they are present in excessive amounts and that some gene mutations cause disease by enhancing the protein's normal activity. A similar disease mechanism has been found in Parkinson's disease, where an extra copy of the normal alpha-synuclein gene can cause disease. In addition, an extra copy of the APP gene (due to an extra copy of chromosome 21) in people with Down syndrome can trigger Alzheimer's disease. Mutations in the alpha-synuclein and APP genes also increase the toxic effects of the proteins they produce. The combination of these findings with the SCA1 discovery shows that neurodegeneration researchers must focus on the normal functions of mutated proteins in order to understand disease, Dr. Zoghbi says.
The researchers are now planning studies to find other proteins that interact with ataxin-1 and to determine if they play a role in SCA1. These proteins could provide additional targets for drug therapy, says Dr. Zoghbi. She and her colleagues also are looking at what ataxin-1 does in normal cells and trying to find ways to increase the level of Gfi-1 in Purkinje cells, perhaps by slowing its degradation. This research could lead to new ways of treating SCA1.
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
*Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen H-K, Rose MF, Venken KJT, Botas J, Orr HT, Bellen HJ, Zoghbi HY. "The AXH Domain of Ataxin-1 Mediates Neurodegeneration through Its Interaction with Gfi-1/Senseless Proteins." Cell, August 26, 2005, Vol. 122, pp. 633-644.
-by Natalie Frazin
Last Modified January 31, 2007