TPASADENA, Calif.-- Huntington's disease is a cruel disorder, destroying nerve cells in the brain that, over time, rob an individual of the ability to walk, talk, and eat. As yet, there is no cure or effective treatment for this hereditary disorder. The end result, then, is death, caused by such complications as infection or heart failure.

Now scientists at the California Institute of Technology have come one step closer to understanding how Huntington's disease develops and how it can be stopped. In a paper to be published in the January 22 issue of the Proceedings of the National Academy of Sciences,Paul H. Patterson , a Caltech professor of biology, postdoctoral scholar Ali Khoshnan, and research assistant Jan Ko have blocked the effects of the disease in cultured cells using antibodies.

Huntington's disease (HD) is caused by a mutation in the protein huntingtin (htt), specifically by the expansion of a site on the protein called polyQ. Such sites induce the production of antibodies that bind with a particular site, normally to kill the antigen. Khoshnan and his colleagues made an antibody that binds to the polyQ site, along with another antibody that binds to a different site, called polyP. The idea was to block either of these sites and see whether the toxic effects of mutant htt, which kills nerve cells in the brain, could be blocked.

"We knew that the polyQ site was critical because when it is expanded by mutation it causes HD," says Patterson." "It was also known that the polyP site on htt might be important for interfering with the functions of other proteins." The investigators produced a modified version of the antibodies that would allow them to be produced inside cells that also carry the toxic mutant htt. They found a key result: when the antibody against the polyP site is produced by cells carrying the mutant htt, the cells are rescued. That is, they are unaffected by the toxic HD protein. In striking contrast, when cells carrying the toxic htt are induced to produce the antibody against the polyQ site, the toxicity of htt is enhanced and the cells die even faster.

Khoshnan and coworkers suggest that the surprising result with the polyQ antibody may be due to the antibody stabilizing a shape of the mutant htt protein in its most deadly form. Most important, though, says Patterson, is that the rescue of the cells that produce the polyP antibody may indicate this is the site of the toxic htt in which the actual killing of cells takes place, and that covering it up with an antibody saves the cell. "Or, an alternative interpretation is that the binding of the antibody preserves the protein in a non-toxic shape," he says.

The researchers have two goals in mind with their work: elucidating the mechanism of neuronal death caused by mutant htt, and devising molecular strategies for blocking its toxic effects.

To arrive at their results, the scientists first developed eight monoclonal antibodies (mAbs), finding the three that either inhibited or exacerbated the toxicity of the mutant Htt protein. They next cloned the antigen-binding "domains" of the three; that is, the portion of the mAbs that does the actual binding. Finally, they caused these domains to be produced inside cells that were also making the mutant htt.

"Potentially, this knowledge could be useful in designing a therapeutic drug, one that covers up that part of the mutant protein that kills healthy cells," says Patterson. "The next stage of the work will be to deliver this antibody into the brains of mice that carry the human mutant gene and that have developed motor symptoms that are related to the disease. We want to see if this antibody can rescue these mice, even after they show signs of the disease. These experiments are, however, just beginning."

HD Researcher Patterson

Source: Caltech press release

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