News Release

Emory University researchers find clue to Huntington's disease mechanism

Peer-Reviewed Publication

Emory University Health Sciences Center

ATLANTA- Huntington's disease, an inherited progressive neurological disorder, often results in the degeneration of neurons in the hypothalamus, a part of the brain that controls appetite and body weight. Scientists at Emory University School of Medicine have discovered how rogue proteins generated by the genetic mistake present in Huntington's disease poison neurons in the hypothalamus. They demonstrate that the mutant proteins interfere with the function of another protein abundant in the hypothalamus –– huntingtin-associated protein-1 (HAP1).

The research is published in the July 30 issue of the Journal of Neuroscience. Lead authors are Shi-Hua Li, MD and Xiao-Jiang Li, PhD, faculty members in Emory's Department of Human Genetics, and Zhao-Xue Yu, PhD, postdoctoral fellow. Dr. Chuxia Deng's laboratory at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) also contributed to the study.

Huntington's disease eventually affects many parts of the brain, but the strongest impact is on the basal ganglia, responsible for coordination of movement. Onset usually occurs between 30 and 50 years of age, and the symptoms become progressively worse over the next 15 years. The main symptoms include loss of control of movement, depression and cognitive impairment. Complications include loss of body weight, heart failure and pneumonia. Huntington's occurs at a frequency of five to seven in a hundred thousand, and some relatives of affected individuals have a 50 percent risk of inheriting the responsible mutation responsible. No effective treatment exists.

Huntington's patients suffer from the genetic equivalent of a skipping record or CD In the gene responsible –– the huntingtin gene –– the enzymes that copy genetic information get stuck and make additional repeats of the same three-letter sequence –– CAG. When the number of repeats grows large enough, the property and function of the protein change. The now-expanded region of the protein clumps together inside the cell, forming aggregates. Dr. Xiaojiang Li says the role of the huntingtin aggregates is still debated by neurologists; it remains unclear whether the aggregates poison cells directly, or are a possibly protective byproduct.

The huntingtin protein normally interacts with the HAP1 protein, which may transport growth-signaling proteins within cells. HAP1, which Dr. Li discovered while working at Johns Hopkins University as a postdoctoral fellow in 1995, is especially abundant in the hypothalamus. Last year Dr. Li's Emory laboratory produced a strain of mice lacking HAP1 and carefully examined the hypothalamus, suspecting it to be the source of the lack of appetite. They found that neurons in the hypothalamus of the HAP1-deficient mice were dying of apoptosis, a self-destruction program activated when cells do not receive proper growth signals. When the scientists examined a mouse model for Huntington's disease (transgenic mice that artificially overproduce the mutant version of huntingtin), they .again found neurons in the hypothalamus dying of apoptosis.

"Previously, scientists could not find neurodegeneration in mice similar to what is present in Huntington's patients," Dr. Li said. "This could be because mice do not live long enough for us to observe effects in the basal ganglia, or it could be because of their early death caused by artificial overproduction of the mutant proteins. But our research confirms that the mouse model works well for the hypothalamus and that HAP-1 loss of function is involved."

In cell culture, the Emory researchers were able to protect normal hypothalamic neurons from the toxic effects of mutant huntingtin by giving them extra HAP1, but Dr. Li cautions that this result might not predict how neurons would be protected in living creatures. Eventually, he suggests, therapeutic strategies that involve bolstering HAP1 function against the assault of the mutant huntingtin might be developed.

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This research was supported by grants from the National Institutes of Health.


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