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UCLA researchers making progress for Huntington’s disease treatment

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Huntington’s disease is a severe neurodegenerative disease that results in death, On April 28, researchers at the Semel Institute for Neuroscience and Human Behavior at UCLA announced that they have made progress in determining the origin of the disease in the brain. The findings could lead to new treatments for Huntington’s disease. The findings were presented online on April 28 in the journal Nature Medicine.

The disease, which strikes approximately 35,000 Americans, is caused by a mutation of a dominant gene, meaning that individuals with one copy of the gene will develop the disease. The mutation is present in every cell in the body; however, it destroys only two types of brain cells. The investigators used a unique approach to switch the gene off in individual regions of the brain; they also examined factors that play a role in causing the disease in mice. The study also o suggests new targets and routes for therapeutic drugs to slow the devastating disease.

“From day one of conception, the mutant gene that causes Huntington’s 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. He added, “Before we can develop effective strategies to treat the disorder, we need to first identify where it starts and how it ravages the brain.”

The disease is passed from parent to child through a mutation in a gene known as huntingtin. Researcher note that a genetic “stutter”, which is a repetitive stretch of DNA at one end of the altered gene, that causes the cell death and brain atrophy that progressively deprives patients of their ability to move, speak, eat, and think clearly. Currently, no cure exists, and individuals with aggressive cases may die in as little as 10 years. The two brain regions that Huntington’s disease destroys are the cortex and the striatum. Significantly more neurons die in the striatum, which is a cerebral region named after its striped layers of gray and white matter. However, it is unclear whether cortical neurons play a role in the disease, including striatal neurons’ malfunction and death.

The investigators employed a unique approach to uncover where the mutant gene wreaks the most damage in the brain. In 2008, Dr. Yang collaborated with co-first author Michelle Gray, a former UCLA postdoctoral researcher now at the University of Alabama, to develop a mouse model for Huntington’s disease. They inserted the entire human huntintin gene, including the stutter, into the mouse genome. The rodents’ brains atrophied and they developed motor and psychiatric-like problems similar to the human patients.

In the new study, Dr. Yang and Nan Wang, co-first author and UCLA postdoctoral researcher, took the model a step further. They integrated a “genetic scissors” that snipped off the stutter and shut down the defective gene; this was done first in the cortical neurons, then in 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 promoted the rodents’ brain atrophy, motor, and psychiatric-like symptoms.

“The genetic scissors gave us the power to study the role of any cell type in Huntington’s,” explained Dr. Wang. She added, “We were surprised to learn that cortical neurons play a key role in initiating aspects of the disease in the brain.” The researchers discovered that reducing huntingtin in the cortex partially improved the rodents’ symptoms. More importantly, shutting down mutant huntingtin in both the cortical and striatal neurons, while leaving it unscathed in the rest of the brain, corrected every symptom they measured in the mice, including motor and psychiatric-like behavioral impairment, as well as brain atrophy.

“We have evidence that the gene mutation highjacks communication between the cortical and striatal neurons,” explained Dr. Yang. He added, “Reducing the defective gene in the cortex normalized this communication and helped lessen the disease’s impact on the striatum… Our research helps to shed lights on an age-old question in the field. Where does Huntington’s disease start? Equally important, our findings provide crucial insights on where to target therapies to reduce mutant gene levels in the brain--we should target both cortical and striatal neurons.”

Some of the researchers’ experimental treatments can be delivered only to limited brain areas, because their properties do not allow them to spread widely throughout the brain. The next phase of the research will be to study how mutant huntingtin affects cortical and striatal neurons’ function and communication; in addition, it will focus on identifying therapeutic targets that may normalize cellular miscommunication to help slow progression of the disease.

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