AUGUST 8, 2005

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By David Secko

A debate is going on in Huntington’s research about whether the hallmark protein aggregates found in the brain of patients actually cause the disease. Now, a new “shortstop” may have found part of the answer.

But this shortstop isn’t an infielder. It’s a new strain of mouse, one with a mutation expected to cause neurodegeneration -- since it’s tailored to make large amounts of the above protein aggregates -- only it doesn’t.

Shortstop mice were recently created by Elizabeth Slow and colleagues at the University of British Columbia. And their unexpected ability to resist neurological damage is causing their creators to suggest the debate is over: protein aggregates do not seem to be toxic in mice.

“This [shortstop] finally ends the debate, showing that aggregates in vivo are not causative of illness,” says Michael Hayden, director of the Centre for Molecular Medicine and Therapeutics at UBC and senior author of a paper describing the mice.

An end to the debate could be important for the future development of drugs to treat Huntington disease, since such drugs are often chosen for their ability to inhibit aggregate formation. Shortstop mice suggest this method may not give the most useful compounds, says Hayden.

Aggregates became a big part of Huntington’s research around half a decade ago when they were found in the brains of patients. They are made of a mutant version of the protein huntingtin and can be easily seen under a light microscope.

“Huntingtin aggregates were only seen in the patients with the illness,” says Hayden, “so people thought it was the cause.” However, it was not altogether clear whether huntingtin aggregates are in fact toxic to the brain, or are simply an indicator of some other pathological process.

Slow and colleagues actually set out to investigate this question by creating a strain of mice that made more of the mutant huntingtin protein. Indeed, they did create such mice, called YAC128, which produces huntingtin aggregates.

But, in a fluke, they also created shortstop.

“We’ve been creating an animal model for this illness and to do that you have to take a very large piece of DNA and inject it into a mouse,” says Hayden, “occasionally the DNA shears and breaks into pieces.”

This is what happened in the creation of shortstop, which although it makes the same amount of huntingtin as YAC128, the version it makes is a smaller protein. Nevertheless, this smaller version still contains the mutation associated with the disease, suggesting these mice should look the same as YAC128 mice.

The serendipitous creation therefore allowed Slow and colleagues to compare YAC128 mice to shortstop mice. They found that both strains formed huntingtin aggregates (these show up as inclusion bodies in neurons). YAC128 mice also had neuronal dysfunctions, in the form of decreases in brain weight and the loss of neurons. However, shortstop mice had no ill effects, despite the presence of huntingtin aggregates in their brains. The results of the study appear in the August 1, 2005 online edition of PNAS.

The results with shortstop mice show that the presence of aggregates and the huntingtin mutation are not sufficient to cause the disease, says Hayden.

However, Hayden does caution that the truncated huntingtin protein in shortstop mice may act slightly differently than the full length version. “The results don’t exclude all the forms of protein folding that can cause the disease,” he says.

Nevertheless, the work makes you question using inclusion bodies of huntingtin as a biomarker for testing drugs to treat Huntington’s, says Hayden,

“Instead we need to look for news ways to screen for these drugs,” he says.

David Secko is a molecular biologist and a science writer, who is currently studying journalism at the University of British Columbia. He thinks Steven Wright was right when he asked: "ok, so what's the speed of dark?" His writing has appeared in The Scientist, The Tyee, Canadian Medical Association Journal, Science's Next Wave and UBC's Thunderbird Magazine. 

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