Science + Technology

UCLA Neuropsychiatric Institute Study Reveals New Insight Into How Huntington’s Disease Attacks the Brain


Scientific theory holds that Huntington's disease (HD) iscaused 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 strongevidence that the mutant protein also elicits toxic interactions fromneighboring cells to provoke the fatal brain disorder. The May 5 editionof Neuron reports the findings.

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

"Our model is the first to show that mutant HD proteinsexert 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 researchersdeveloped two sets of mice with the human HD gene mutation. The first group wasengineered 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 braincells.

The scientists reasoned that if the mutant protein triggeredthe disease only from within the target cells, the second set of mice woulddisplay significant signs of the disorder. If HD required toxic interactionsamong cells throughout the brain, however, these same mice would show little orno signs of the disorder.

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

"This is the first direct genetic evidence to demonstratethat abnormal interactions between cells can significantly contribute to braincell death in a living mouse model of Huntington's disease," Yang said.

Yang's team now is trying to pinpoint which of theneighboring cells generate Huntington's disease.

"Our next step will be determining how neighboring cellsinfluence target cells and cause their death," he said. "Once we understand howthese cells interact, the knowledge may lead to new therapeutic strategies totreat Huntington's disease."

Huntington'sdisease is a genetic brain disorder that usually strikes in mid-life, but canalso attack the elderly and children as young as 2. Slowly depriving a personof their ability to think, speak, walk and swallow, the disease robs the personof their independence, leading to death within 10 to 25 years.

Every carrier of the HD gene mutation will develop thedisease. Each child of a parent with Huntington's disease has a 50 percent riskof inheriting the illness. In the United States, the disease strikes 30,000people and places another 150,000 persons at risk. The disorder affects malesand 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 thestudy.

Yang's coauthors included XiaofengGu, Victor Lo, Weizheng Wei and Istvan Mody of UCLA; Chenjian Li ofCornell University; Shiaoching Gong and Nathaniel Heintz of Rockefeller University; Shi-HuaLi and Xiao-Jiang Li of Emory University; and Takuji Iwasato and Shigeyoshi Itohara of Riken Brain Science Institute. Iwasato also is affiliated with the Presto Japan Scienceand Technology Agency.

The UCLA NeuropsychiatricInstitute is an interdisciplinary research and education institute devoted tothe understanding of complex human behavior, including the genetic, biological,behavioral and sociocultural underpinnings of normalbehavior, and the causes and consequences of neuropsychiatricdisorders. In addition to conducting fundamental research, the institutefaculty seeks to develop effective treatments for neurological and psychiatricdisorders, improve access to mental health services, and shape national healthpolicy regarding neuropsychiatric disorders. Moreinformation is available online at and at



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