Tricking Huntington's Disease Gene to Shut Off

Researchers find technique works in mice

By Jamie Talan
October 22, 2002

From the Fall 2002 issue of Hopes & Dreams, newsletter of the Illinois Chapter, Huntington's Disease Society of America.

Researchers have devised a clever genetic technique in mice that can regulate the production of the abnormal protein that causes Huntington's disease.

Ai Yamamoto, a researcher at Memorial Sloan-Kettering Cancer Center, created an animal model that exhibits all the signs of the lethal disease: brain damage and impaired movement. When the mutant gene is shut off, toxic protein deposits clear out and the animal improves substantially. Yamamoto presented her findings last week at the American Neurological Association's annual meeting in Manhattan.

The study raises many questions about the nature of neurodegenerative diseases like Huntington's and Alzheimer's and whether these diseases can be reversed in humans.

"The work is extraordinary," said Dr. Anne B. Young, a Huntington's investigator at Massachusetts General Hospital in Boston. "... We've always thought that neurodegeneration was irreversible. Turning gene expression off can clear out the pathology and improve function."

In Yamamoto's mouse model, the continuous production of mutant Huntington's protein was necessary to trigger disease.

"We don't yet know the mechanism that we are touching that allows for this recovery," said Yamamoto, who did the work at Columbia University College of Physicians and Surgeons. She has joined Memorial Sloan-Kettering, where her work continues.

Since the Huntington's gene was discovered in 1993, investigators worldwide have focused on unraveling the mechanisms that lead to the devastating and fatal condition. Roughly 30,000 Americans have Huntington's, and 150,000 more people carry the disease gene but have yet to become sick. Only one mutated gene is needed to trigger the disease.

Huntington's is the most common of the so-called trinucleotide repeat disorders. No one knows for sure what role the normal protein plays, but when a small amino acid gene sequence is repeated over and over like a broken record, the protein is overproduced by the gene, causing disease. Up to 35 repeats of the amino acid glutamine is normal and more than 37 results in the disorder. This abnormal protein targets a specific group of brain cells in the striatum that regulate movement, thought and behavior.

Dr. James Gusella, a scientist at Massachusetts General Hospital who discovered the Huntington's gene on chromosome 4, said it is still not known how the gene defect leads to symptoms. Scientists have discovered that the mutant protein is abnormally folded, which alters its structure and function. But just how it leads to the damage and death of the medium spiny neurons in the striatum, and then how that causes symptoms, is not clear.

It seems to be the misfolding that leads to the buildup of protein in the cells, Gusella said.

Symptoms - involuntary, dance-like movements and cognitive problems - usually begin in the 30s and 40s, but people with more repeats of glutamine develop the disease earlier. There are no treatments.

It's too early to say whether a similar approach to manipulate the mutant gene, or its abnormal protein, would prevent or reverse the disease in humans. But scientists say any treatment would be best designed to target the disease's early stages.

"My belief is that if we could prevent these protein aggregates from forming, we could prevent the disease," said Carl Johnson, executive director of the Cure Huntington's Disease Initiative at the Hereditary Disease Foundation.

"It's magnificent work," said Columbia's Nancy Wexler, a Huntington's disease researcher and president of the Hereditary Disease Foundation, which funded the study.

Copyright (c) 2002, Newsday, Inc. Reprinted with permission.

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Created: Dec. 27, 2002
Last updated: Dec. 7, 2010