Pitt researchers describe molecular '2-step' leading to protein clumps of Huntington...(f how the aggregation behavior of huntin...)

They found that longer polyglutamine sequences have the ability to disrupt the structure of a neighboring region, 17 amino acids long, at the beginning of the protein known as the N-terminus. That sets the stage for new physical interactions with the rest of the huntingtin protein that drive it to aggregate.

"If the N-terminus is not there, huntingtin makes clumps very slowly, even if the polyglutamine stretch is rather long," Dr. Wetzel noted. "When the N-terminus is disrupted by its polyglutamine neighbor, it takes a lead role in the aggregation process, with the polyglutamine then following to consolidate and stabilize the clumps a kind of 'aggregation two-step'."

The choreography might be similar in other polyglutamine diseases, meaning physical disruption of neighboring regions may influence the tendency for the protein to clump, he added. More research is needed to establish whether the aggregates cause disease or are merely a marker for it, and to try to develop treatments that can redirect the protein dance or perhaps halt it entirely. "For those of us interested in developing therapeutics," Dr. Wetzel notes, "the strong role played by the N-terminus in initiating aggregation gives us another possible molecular target."

Huntington's disease is an inherited disease in which progressive degeneration of certain brain neurons causes uncontrolled writhing, twisting and jerking movements, and cognitive and psychiatric problems. It was once called Huntington's "chorea", from a Greek word for dance.

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