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.
Studying the action of ataxin-1 in mice and fruit flies gave her the answer. Putting the abnormal protein with 80 repeats into mice forces degeneration of special neurons called Purkinje cells and results in the mice developing the ataxia or loss of balance. Yet putting large amounts of the normal protein with 30 repeats into mice also results in abnormal neuron function, she said. Putting the fly form of the protein in flies can also induce neuron degeneration, even though the fly protein does not have the repeated sequences.
Research in the laboratory of Dr. Hugo Bellen, professor of molecular and human genetics and a Howard Hughes Medical Institute investigator at BCM, helped shed light on what ataxin-1 does by finding that a protein he studies called senseless binds ataxin-1.
Senseless is important in development of the peripheral nerve system in flies.
The Zoghbi-Bellen team found that ataxin-1 decreases levels of senseless and affects the development of the nervous system. Equally important, they found that ataxin-1also decreases levels of the senseless counter-part in mice, the Gfi-1 protein. Lowering Gfi-1 levels leads to Purkinje cell degeneration.
What is interesting is that both the normal and mutated forms of ataxin-1 have this effect but the mutant form does it more potently. "We are learning that this phenomenon of a normal protein acting as a toxin when in high levels is not unique," she said. For example, alpha-synuclein, a protein mutated in rare forms of inherited Parkinson's disease, also sometimes accumulates in cells of patients with the ordinary form of the disease. In families that have extra copies of the normal gene, the toxic effects of high protein levels are apparent.
"The same is true of the amyloid precursor protein that is mutated in some rare forms of Alzheimer's disease," she said. "Three normal copies of amyloid precursor protein can cause the enhanced levels of the protein and its byproduct that are toxic to brain cells."
Others who contributed to this paper include: Drs. Hirsohi Tsuda, Hamed Jafar-Nejad, Hung-Kai Chen, and Juan Botas; and Akash J Patel, Yaling Sun, Matthew F Rose, and Koen J.T Venken, all of BCM, and Dr. Harry T Orr of the University of Minnesota.