Scientists unveil two molecular steps leading to protein clumps of Huntington’’s disease

March 9th, 2009 - 2:31 pm ICT by ANI  

London, March 9 (ANI): Scientists at the University of Pittsburgh School of Medicine say that they have deconstructed 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.
Dr. Ronald Wetzel, a professor in the Department of Structural Biology, points out that 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.
The researcher has revealed that the affected protein in Huntington’’s disease is called huntingtin.
According to him, 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.
However, the odds of contracting Huntington’’s disease increase significantly 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. 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,” Nature magazine quoted Dr. Wetzel as saying.
In the current study, the researchers worked out the details of how the aggregation behaviour of huntingtin depends, in a surprisingly intricate way, on the neighboring segments of amino acid sequence flanking the polyglutamine.
The research team observed 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.
According to the researchers, 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. 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”,” Dr. Wetzel noted.
The researcher believes that the choreography may be similar in other polyglutamine diseases, which means that physical disruption of neighbouring regions may influence the tendency for the protein to clump.
He warranted further studies 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, the strong role played by the N-terminus in initiating aggregation gives us another possible molecular target,” Dr. Wetzel notes.
An article on this research work has been published in the online edition of the journal Nature Structural and Molecular Biology. (ANI)

Tags: , , , , , , , , , , , , , , , , , , ,

Posted in Health Science |