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January 22, 2001

Yerkes' Smith hunts for Huntington's disease clues

By Poul Olson

A team of Yerkes neuroscientists led by Yoland Smith are mapping brain receptors suspected of playing a role in the death of neurons associated with Huntington’s disease. The research, presented in November at the Society for Neuroscience’s annual conference in New Orleans, could shed new light on how the debilitating neurodegenerative disease develops.

A genetically inherited illness, Huntington’s is characterized by motor and cognitive impairments.

The disease first becomes evident in middle age and develops over 15 to 20 years, killing 95 percent of the neurons in the striatum, an area of the brain that channels information from the cerebral cortex to the basal ganglia. The resulting interference in communication between the cerebral cortex and the basal ganglia disrupts cognitive and motor functions. In addition to developing psychiatric problems, many people with Huntington’s experience chorea—a motor impairment characterized by jerky, uncontrollable and often violent movements of the limbs.

How this neuronal death actually occurs has long eluded researchers. New clues emerged in 1997 following the discovery of a mutation in the gene that encodes for the brain’s receptors for kainate, a powerful neurotoxin. This deviation occurs among a special subset of people with Huntington’s.
Kainate receptors, a subtype of glutamate receptors, are dispersed widely throughout the central nervous system. Their precise locations and function, however, are poorly understood.

In their research, Smith and his team have used electron microscopy to locate the receptors in the striatum of rhesus macaques. Most recently, they made an intriguing discovery of kainate receptors in cortical terminals that use glutamate as a neurotransmitter.

“It’s very unusual for kainate receptors to be located there,” said Smith. “This suggests a role for the receptors in modulating the release of glutamate into the striatum and ultimately mediating the death of striatal neurons.”

If Huntington’s causes kainate receptors to be hyperactivated, they could release too much glutamate (an excitatory neurotransmitter) into the striatum, Smith believes. At excess levels, glutamate kills neurons.

While mapping the location of the kainate receptors, Smith and his team, in collaboration with other colleagues, intend to study their function using a new class of drugs that selectively bind to these receptors.

“We don’t know where these receptors are or what they do,” said Smith.

Huntington’s disease belongs to the class of neurodegenerative illnesses that includes Alzheimer’s and Parkinson’s diseases. In 1993, the discovery of a mutated gene that causes Huntington’s was heralded as a breakthrough that would soon lead to a cure.

Scientists believed drugs could be developed to preferentially target the Huntingtin protein in striatal neurons that degenerate. These hopes were dashed when researchers discovered that the protein occurs abundantly throughout the central nervous system.

Huntington’s disease typically strikes between age 40 and 50 and can take as long as two decades to progress fully. Genetic tests can identify those at risk for Huntington’s, but having the Huntington’s gene does not necessarily mean a person will develop the disease.

The complexity of Huntington’s symptoms makes treating the disease difficult. Smith explained that medications designed to ameliorate motor dysfunction, for instance, often have adverse side effects on cognition.

Although there are no new treatments on the horizon, Smith hopes that understanding the role of kainate receptors in the Huntington’s process eventually could yield new targets for medications.

“A good compound that selectively targets kainate receptors could control the release of glutamate into the striatum,” Smith said. “This disease could potentially be thwarted before it has a chance to start on its path of destruction.”

The Huntington’s disease research program is funded by a four-year, $600,000 grant from the U.S. Army Medical Research and Materiel Council.


Back to Emory Report Jan. 22, 2001