Solving The Mystery Of Mutated Proteins And The Brain

Dr. Huda Zoghbi and her colleagues have determined that a geneticmutation actually enhances the normal activity of a protein, and in thecase of ataxin-1, the disease spinocerebellar ataxia type 1 results.While this disease is rare, the finding may be important inunderstanding similar, more common diseases, said Zoghbi, professor ofpediatrics and molecular and human genetics at BCM and Howard HughesMedical Institute investigator.

"What has been gradually revealed throughout the years is thatby studying rare diseases such as this one, the findings are ofteninstructive about the more common ones," said Zoghbi.

That is important as neurodegenerative disorders becomeincreasingly common in an aging population. For example, an estimated4.5 million Americans have Alzheimer's disease, a number that hasdoubled since 1980 and is expected to continue to rise to as many as 16million by the year 2050. "Understanding what happens to brain cells inthese diseases is a big challenge," said Zoghbi.

As she found previously, in spinocerebellar ataxia type 1, theataxin-1 gene has an abnormally high number of repeated bases, thedistinctive chemical ingredients found in genetic material. In thiscase, when C (cytosine), A (adenine) and G (guanine) are repeated morethan 35 times, the protein is toxic. (CAG causes production of an aminoacid 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 glutaminestring actually increases the activity of the "business part of theprotein" and locks it into a shape that causes the protein toaccumulate to toxic levels in cells.

Studying the action of ataxin-1 in mice and fruit flies gaveher the answer. Putting the abnormal protein with 80 repeats into miceforces degeneration of special neurons called Purkinje cells andresults in the mice developing the ataxia or loss of balance. Yetputting large amounts of the normal protein with 30 repeats into micealso results in abnormal neuron function, she said. Putting the flyform of the protein in flies can also induce neuron degeneration, eventhough the fly protein does not have the repeated sequences.

Research in the laboratory of Dr. Hugo Bellen, professor ofmolecular and human genetics and a Howard Hughes Medical Instituteinvestigator at BCM, helped shed light on what ataxin-1 does by findingthat 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 ofsenseless and affects the development of the nervous system. Equallyimportant, they found that ataxin-1also decreases levels of thesenseless counter-part in mice, the Gfi-1 protein. Lowering Gfi-1levels leads to Purkinje cell degeneration.

What is interesting is that both the normal and mutated formsof 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 atoxin when in high levels is not unique," she said. For example,alpha-synuclein, a protein mutated in rare forms of inheritedParkinson's disease, also sometimes accumulates in cells of patientswith the ordinary form of the disease. In families that have extracopies of the normal gene, the toxic effects of high protein levels areapparent.

"The same is true of the amyloid precursor protein that ismutated in some rare forms of Alzheimer's disease," she said. "Threenormal copies of amyloid precursor protein can cause the enhancedlevels of the protein and its byproduct that are toxic to brain cells."

Others who contributed to this paper include: Drs. HirsohiTsuda, Hamed Jafar-Nejad, Hung-Kai Chen, and Juan Botas; and Akash JPatel, Yaling Sun, Matthew F Rose, and Koen J.T Venken, all of BCM, andDr. Harry T Orr of the University of Minnesota.