BETHESDA, Md. - Researchers at the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH) report in the October issue of Nature Genetics the development of the best mouse model yet of Huntington's disease (HD). The models are analogous to both the behavioral and pathological changes of the disease.
Since the discovery in 1993 of the gene alteration leading to HD, scientists have sought to understand why the abnormal protein produced by the altered gene leads to mid-life degeneration of specific brain cells, dramatic behavior changes and premature death for those who possess the alteration.
These new mouse models provide scientists a tool for studying the development of HD and other related diseases, and perhaps even the process of apoptosis (programmed cell death), which is essential to life.
Progress in treating HD has been slow in that tissues from the brains of HD patients are available for study only after death. With the brains of the new mice closely resembling those of HD patients, the researchers believe that methods of developing treatment should increase, and that scientists will now be able to delve far more deeply into the disease process.
The abnormal movements and behavior the mice display -- running in circles, performing backflips, engaging in other hyperkinetic behavior -- correlates with loss of neurons in the striatum, cortex and other brain regions where HD patients also lose brain cells.
The mice are expected to be useful for screening potential pharmacological treatments for HD, and for testing other therapies, including ones that might assist neuron survival.
"Current treatments for Huntington's disease only address the symptoms, and do nothing to slow the progress of neuronal cell death," said Dr. Danilo A. Tagle, head of NHGRI's Molecular Neurogenetics Section, and the paper's corresponding author. "If treatments can be developed, based on this animal model, to prevent or delay the cell death and the debilitating symptoms of HD, then that would be the best-case scenario."
HD is one of several genetic disorders known as the triplet-repeat diseases caused by excessive repetition of the CAG nucleotide sequences that code for glutamines. In these diseases and HD, however, more than just the repeated sequences appears to be necessary to produce the disease.
"We think the rest of the protein may have a role in dictating what populations of neurons die, and which ones survive," Tagle said.
The normal HD protein is found in nearly all body cells, but only specific brain cells die in HD. Why? The NHGRI researchers suspect the abnormal HD protein is interacting with other proteins found only in those cells, and that this interaction triggers cell death. Perhaps, the researchers speculate, the altered HD protein is shaped abnormally, and it clings to the other proteins, preventing them from conducting their assigned tasks.
NHGRI researchers are now trying to answer that question by studying the new mice to identify key proteins that interact with the HD proteins.
"These mice will be terrific models for examining the early events that occur in HD and how this ultimately leads to cell death; that's still a very open question at this point," Tagle said.
NHGRI oversees the NIH's role in the Human Genome Project, an international research effort to develop tools for gene discovery.
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Last Reviewed: February 25, 2012