Scientists Hunt Down Origin of Huntington's Disease in the Brain and Provide Insights to Help Deliver Therapy

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Newswise The gene mutation that causes Huntingtons disease appears in every cell in the body, yet kills only two types of brain cells. Why? UCLA scientists used a unique approach to switch the gene off in individual brain regions and zero in on those that play a role in causing the disease in mice.

Published in the April 28 online edition of Nature Medicine, the research sheds light on where Huntingtons starts in the brain. It also suggests new targets and routes for therapeutic drugs to slow the devastating disease, which strikes an estimated 35,000 Americans.

From day one of conception, the mutant gene that causes Huntingtons appears everywhere in the body, including every cell in the brain, explained X. William Yang, professor of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience and Human Behavior at UCLA. Before we can develop effective strategies to treat the disorder, we need to first identify where it starts and how it ravages the brain.

Huntington's disease is passed from parent to child through a mutation in a gene called huntingtin. Scientists blame a genetic stutter -- a repetitive stretch of DNA at one end of the altered genefor the cell death and brain atrophy that progressively deprives patients of their ability to move, speak, eat and think clearly. No cure exists, and people with aggressive cases may die in as little as 10 years.

Huntingtons disease targets cells in two brain regions for destruction: the cortex and the striatum. Far more neurons die in the striatuma cerebral region named after its striped layers of gray and white matter. But its unclear whether cortical neurons play a role in the disease, including striatal neurons malfunction and death.

Yangs team used a unique approach to uncover where the mutant gene wreaks the most damage in the brain.

In 2008, Yang collaborated with co-first author Michelle Gray, a former UCLA postdoctoral researcher now at the University of Alabama, to engineer a mouse model for Huntingtons disease. The scientists inserted the entire human huntintin gene, including the stutter, into the mouse genome. As the animals brains atrophied, the mice developed motor and psychiatric-like problems similar to the human patients.

In the current study, Yang and Nan Wang, co-first author and UCLA postdoctoral researcher, took the model one step further. They integrated a genetic scissors that snipped off the stutter and shut down the defective genefirst in the cortical neurons, then the striatal neurons and finally in both sets of cells. In each case, they measured how the mutant gene influenced disease development in the cells and affected the animals brain atrophy, motor and psychiatric-like symptoms.

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Scientists Hunt Down Origin of Huntington's Disease in the Brain and Provide Insights to Help Deliver Therapy