"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 can significantly contribute to brain cell death in a living mouse model of Huntington's disease," said Yang.
Yang's team is now trying to pinpoint which of the neighboring cells generate Huntington's disease.
"Our next step will be determining how neighboring cells influence target cells and cause their death," he said. "Once we understand how these cells interact, the knowledge may lead to new therapeutic strategies to treat Huntington's disease."
Huntington's disease is a genetic brain disorder that usually strikes in mid-life, but can also attack the elderly and children as young as 2. Slowly depriving a person of their ability to think, speak, walk and swallow, the disease robs the person of their independence, leading to death within 10 to 25 years.
Every carrier of the HD gene mutation will develop the disease. Each child of a parent with Huntington's disease possesses a 50 percent risk of inheriting the illness. In the United States, the disease strikes 30,000 people and places another 150,000 persons at risk. The disorder affects males and females equally and crosses all ethnic and racial boundaries.
The National Institute of Neurological Disorders and Stroke, Hereditary Disease Foundation and Cisneros Children's Foundation funded the study.
Yang's coauthors included Xiaofeng Gu, Victor Lo, Weizheng Wei and Istvan Mody of UCLA, Chenjian Li of Cornell University, Shiaoching Gong and Nathaniel Heintz of Rockefeller University, Shi-Hua Li and Xiao-Jiang Li of Emory University, and Takuji Iwasato and Shigeyoshi Itohara of Riken Brain Science Institute. Iwasato is also affiliated with the Presto Japan Science and Technology Agency.
The UCLA Neuropsychiatric Institute is an interdisciplinary research and education institute devoted to the understanding of complex human behavior, including the genetic, biological, behavioral and sociocultural underpinnings of normal behavior, and the causes and consequences of neuropsychiatric disorders. In addition to conducting fundamental research, the institute faculty seeks to develop effective treatments for neurological and psychiatric disorders, improve access to mental health services, and shape national health policy regarding neuropsychiatric disorders. More information is available online at http://www.npi.ucla.edu/ and at http://www.placebo.ucla.edu/.
Journal
Neuron