Dr. Huda Zoghbi and her colleagues have determined that a genetic mutation actually enhances the normal activity of a protein, and in the case of ataxin-1, the disease spinocerebellar ataxia type 1 results. While this disease is rare, the finding may be important in understanding similar, more common diseases, said Zoghbi, professor of pediatrics and molecular and human genetics at BCM and Howard Hughes Medical Institute investigator.
"What has been gradually revealed throughout the years is that by studying rare diseases such as this one, the findings are often instructive about the more common ones," said Zoghbi.
That is important as neurodegenerative disorders become increasingly common in an aging population. For example, an estimated 4.5 million Americans have Alzheimer's disease, a number that has doubled since 1980 and is expected to continue to rise to as many as 16 million by the year 2050. "Understanding what happens to brain cells in these diseases is a big challenge," said Zoghbi.
As she found previously, in spinocerebellar ataxia type 1, the ataxin-1 gene has an abnormally high number of repeated bases, the distinctive chemical ingredients found in genetic material. In this case, when C (cytosine), A (adenine) and G (guanine) are repeated more than 35 times, the protein is toxic. (CAG causes production of an amino acid called glutamine.)
"It's like having a story in which three words are repeated over and over," said Zoghbi. "Why does the story change?"
She and her colleagues now think that the expanded glutamine string actually increases the activity of the "business part of the protein" and locks it into a shape that causes the protein to accumulate to toxic levels in cells.