New insights into how Huntington's disease attacks the brain

Scientific theory holds that Huntington's disease (HD) is caused by a mutant protein that arises within brain cells and kills them, triggering the genetic neurological disorder. Now a new UCLA Neuropsychiatric Institute study reveals the first strong evidence that the mutant protein also elicits toxic interactions from neighboring cells to provoke the fatal brain disorder. The May 5 edition of Neuron reports the findings.

"This is really important because most current disease models and drug development efforts rely on the assumption that Huntington's disease arises from within the target brain cells," explained Dr. William Yang, assistant professor at the UCLA Neuropsychiatric Institute and a member of the Brain Research Institute.

"Our model is the first to show that mutant HD proteins exert their influence on brain cells located near the target cells," he said. "These neighboring cells then interact with the target cells to spark disease."

To pinpoint the disorder's cellular origin, UCLA researchers developed two sets of mice with the human HD gene mutation. The first group was engineered to trigger production of the mutant HD protein throughout the brain. The second set of mice produced the mutant HD protein only in the target brain cells.

The scientists reasoned that if the mutant protein triggered the disease only from within the target cells, the second set of mice would display significant signs of the disorder. If HD required toxic interactions among cells throughout the brain, however, these same mice would show little or no signs of the disorder.

When comparing the two groups, the UCLA team discovered that the first set of mice demonstrated problems with motor control and showed visible degeneration of the target brain cells. In contrast, the second set of mice showed little signs of the disease.

"This is the first direct genetic evidence to demonstrate that abnormal interactions between cells

Contact: Elaine Schmidt
University of California - Los Angeles

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