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Too Much of Normal
by Rabiya S. Tuma
Hiroshi Tsuda (left), Huda Zoghbi, and colleagues discovered a new factor in the development of neurodegenerative disorders.
Huda Y. Zoghbi long wanted to know how one mutant protein can wreak such havoc in people who have spinocerebellar ataxia type 1 (SCA1). A chance observation by a first-year graduate student shed light on the problem—in what might be a case where too much good is actually bad.
SCA1 belongs to a group of neurodegenerative disorders called the polyglutamine diseases, each of which is characterized by a mutant protein with an abnormally long stretch of a single amino acid—glutamine.
"Most people have naturally focused on the polyglutamine tract [that stretch of glutamine repeats] when studying the pathogenesis of these polyglutamine diseases," says Zoghbi, an HHMI investigator at Baylor College of Medicine in Houston. But she sees things differently. If each disorder causes a unique constellation of symptoms, Zoghbi reasons, then the shared polyglutamine tract cannot be the only part of the protein that is culpable. The challenge, then, is how to identify other regions of the protein—ataxin-1 in the case of SCA1—that contribute to the problem.
A lucky break came when first-year graduate student Matthew F. Rose was deciding whose lab to join for his dissertation work—Zoghbi's or that of Hugo J. Bellen, also an HHMI investigator at Baylor, who works on development of the nervous system in the fruit fly Drosophila melanogaster. While trying out Bellen's lab, Rose combed through the results of an experiment, designed by postdoctoral fellow Hamed Jafar-Nejad, to identify proteins that interact with the Drosophila protein Senseless. Rose noticed in particular that dAtx-1—the fly equivalent of ataxin-1—binds to senseless.
Photo: Rocky Kneten
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