Scientists at the National Institutes of Health, in collaboration with a Vanderbilt University Medical Center neuropathologist, have genetically engineered and studied mice that mimic the behavioral and pathological changes of Huntington's disease.
The achievement holds promise as an important step in understanding the role of the Huntington's disease (HD) gene, which was discovered in 1993, and potentially in the ultimate development of treatments for the devastating neurological disorder.
The researchers report their findings in the October issue of the scientific journal Nature Genetics. The work was funded by the NIH.
"This transgenic animal appears to be the most faithful model to study Huntington's disease thus far," said co-author Dr. William Whetsell, professor of Pathology and Psychiatry at Vanderbilt. Whetsell assessed the neuropathological changes in the brains of the mice and found them to be similar to those seen in human Huntington's disease.
"The striking thing about this work is that these animals appear to be affected in what one might call a 'dose-dependent' fashion, as are patients with Huntington's disease," Whetsell said. "The greater the load, so to speak, of the abnormal gene, the more pronounced the symptoms. The course of presentation of the clinical symptoms very closely parallels that seen in patients with Huntington's. And the neuropathological changes found in these animals -- particularly those with the most pronounced clinical symptoms -- are very similar to those seen in the brains of patients with Huntington's disease. Even the same brain regions appear to be predominantly affected."
Huntington's disease is an inherited disorder that results from the genetically programmed degeneration of cells in certain areas of the brain. Symptoms, which typically begin in middle age, may vary considerably from person to person, but over time, the disease robs the person's ability to think or move. Drugs may be prescribed to control some of the emotional or movement problems related to Huntington's disease, but there is no cure.
In Nature Genetics, the authors describe the development of a line of transgenic mice that express the complete human HD gene. Transgenic animal models are created by injecting foreign genes into the embryonic animals. The animals' cells then follow the "instructions" of the foreign gene. Transgenic animal models are developed in an effort to duplicate human disease, with the goal of better understanding its development and studying potential treatments.
The genetic defect that produces Huntington's disease results when a particular sequence of DNA is abnormally repeated dozens of times. The more "repeats" of this sequence of DNA, the greater the odds that the person will develop Huntington's disease.
The NIH scientists from the National Human Genome Research Institute inserted into the mice the HD gene that repeated this DNA sequence 16, 48 or 89 times. The mice were bred through several generations.
The transgenic mice with 48 or 89 repeats of this sequence developed progressive behavioral and motor dysfunction. They also exhibited the loss of neurons in specific areas of the brain.
"The mice develop early symptoms after eight to 10 weeks, seen first as hyperactivity and some changes in posture," Whetsell said. "They become quite restless, then begin constant circling. After a time, they gradually slow down, become inactive and lose interest in their surroundings. Then they become virtually inert and die.
"There is a remarkable correlation between the genotype -- which HD gene was expressed -- and the behavioral abnormality and the degeneration found in the brains of these animals."
Researchers hope to learn more about how the abnormality in the HD gene leads to the destruction of neurons in the brain, Whetsell said. One theory is that the repeated sequence prompts some sort of enzymatic disorder.
Senior author of the paper is Dr. Danilo A. Tagle, director of the Neurogenetics Section of the National Human Genome Research Institute. Other NIH collaborators are P. Hemachandra Reddy, Maya Williams, Vinod Charles, Lisa Garrett, Lisa Pike-Buchanan and Georgina Miller.