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UCLA researchers report treatment for Huntington’s disease

UCLA researchers have made a breakthrough that may lead to effective therapies for Huntington's disease
UCLA researchers have made a breakthrough that may lead to effective therapies for Huntington's disease
Robin Wulffson, MD

Huntington’s disease is a devastating genetic disorder that progressively destroys neurons in the brain. It usually strikes in adulthood and gradually deprives patients of their ability to walk, speak, swallow, breathe, and think clearly. To date, a cure is not available; however UCLA researchers have made a breakthrough that may lead to effective therapies for the condition. They published their findings online on March 30 in the journal Nature Neuroscience.

The investigators conducted a study in mice that increased the ability of a specific type of cell to absorb potassium in the brain. The research laboratories of Baljit Khakh, a UCLA professor of physiology and neurobiology, and Michael Sofroniew, a UCLA professor of neurobiology, joined forces at the David Geffen School of Medicine at UCLA to gain understanding of the role that astrocytes play in the development of the disorder. Astrocytes are large, star-shaped cells that are present in the brain and spinal cord. Dr. Khakh explained, “Astrocytes appear in the brain in equal numbers to neurons yet haven’t been closely studied. They enable neurons to signal each other by maintaining an optimal chemical environment outside the cells. We used two mouse models to explore whether astrocytes behave differently during Huntington’s disease.”

The first model created a scenario of an aggressive, early-onset type of Huntington’s disease; the second created one of a slow-developing version. The researchers examined how the mutation affected astrocytes in the brain. They focused on the astrocytes’ interaction with a type of neuron that plays a major role in coordinating movement. In both models, astrocytes with the defective gene exhibited a measurable decrease in Kir4.1, which is a protein that allows the astrocyte to absorb potassium through the cell membrane. This resulted in an excess of potassium outside the cell; thus, disrupting the chemical balance and increasing the nearby neurons’ “excitability,” or capacity to fire. Dr. Sofroniew explained, “We suspect that the gene mutation contributes to Huntington’s disease by reducing Kir4.1 levels in the astrocytes. “This, in turn, reduces the cell’s uptake of potassium. When excess potassium pools around neurons, they grow oversensitive and fire too easily, disrupting nerve cell function and ultimately the body’s ability to move properly. This may contribute to the jerky motions common to Huntington’s disease.”

To test their theory, the researchers assessed what would happen if they artificially increased Kir4.1 levels inside the astrocytes. The results were extremely significant. Dr. Khakh said, “Boosting Kir4.1 in the astrocytes improved the mice’s ability to walk properly. We were surprised to see the length and width of the mouse’s stride return to more normal levels. This was an unexpected discovery.” Dr. Sofroniew added, “Our work breaks new ground by showing that disrupting astrocyte function leads to the disruption of neuron function in a mouse model of Huntington’s disease. Our findings suggest that therapeutic targets exist for the disorder beyond neurons.”

The authors note that their findings add significant understanding to one of the mechanisms involved in Huntington’s disease and also provide more general implications. Dr. Khakh explained, “We’re really excited that astrocytes can potentially be exploited for new drug treatments. Astrocyte dysfunction also may be involved in other neurological diseases beyond Huntington’s.”

The next phase of the research involves clarifying the mechanism whereby Kir4.1 levels are reduced and to assess how this alters neuronal networks.

Huntington's disease is a neurodegenerative genetic disorder that affects one in every 20,000 Americans. It is caused by a dominant gene, meaning that only one copy of the gene will produce the disease and the child of an affected parent has a 50% chance of inheriting it. . It is much more common in individuals of Western European descent than in those of Asian or African ancestry. The disease can affect both men and women. Physical symptoms of Huntington's disease can begin at any age from infancy to old age; however, it usually appears between 35 and 44 years of age. Approximately 6% of cases start before the age of 21 years.

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