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Pitt researchers describe molecular '2-step' leading to protein clumps of Huntington's disease
Date:3/8/2009

PITTSBURGH, March 8 In a paper published in the early online version of Nature Structural and Molecular Biology, researchers at the University of Pittsburgh School of Medicine deconstruct the first steps in an intricate molecular dance that might lead to the formation of pathogenic protein clumps in Huntington's disease, and possibly other movement-related neurological disorders.

Huntington's is one of 10 diseases in which a certain protein, different for each disease, contains polyglutamine, a stretch of repeating blocks of the amino acid glutamine, explained Ronald Wetzel, Ph.D., professor in the Department of Structural Biology and member of the Pittsburgh Institute for Neurodegenerative Diseases at the University of Pittsburgh School of Medicine. The affected protein in Huntington's disease is called huntingtin.

Most people have a huntingtin protein whose polyglutamine segment contains 20 or so glutamines, and even a polyglutamine with as many as 35 repeats may not cause Huntington's symptoms. But the risk of developing Huntington's disease rises sharply in individuals whose polyglutamine sequences are only slightly larger. A block of 40 repeats, for example, is associated with a very high likelihood of having the disease.

"To a protein chemist, this is a fascinating situation," Dr. Wetzel said. "Polyglutamine doesn't seem to play a sophisticated role in these proteins, and it doesn't have a defined structure. Yet by changing its length to only a very slight extent, it takes on some new physical properties that somehow initiate diseases."

One consequence of the lengthening is protein aggregation, or clumping, a feature that consistently appears in brain cells of patients who have one of these neurodegenerative diseases. Many research groups, including Dr. Wetzel's, study how polyglutamine expansion alters the huntingtin protein's behavior.

In its most recent studies, the Pitt team worked out the details o
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Contact: Anita Srikameswaran
SrikamAV@upmc.edu
412-647-3555
University of Pittsburgh Schools of the Health Sciences
Source:Eurekalert

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