LONDON - If transgenic mice that provide a model of Huntington's disease take more exercise, are exposed to novel objects and are given cardboard to shred, they take significantly longer to develop symptoms of disease. The discovery could, researchers predict, one day lead to better drugs to treat people who suffer from the disease.
Anton van Dellen, Rhodes scholar at the University Laboratory of Physiology at the University of Oxford in Oxford, UK, told BioWorld International: "The exciting thing about this finding is that this is the first time anything has been described which delays the onset of the disease. This work offers a first step toward being able to say that this disease is not inexorable and is not unremitting, but that it may be possible to delay its onset."
Van Dellen, together with colleagues at the University of Oxford and at the University of Natal Medical School in Durban, South Africa, report their findings in a "Brief Communication" in the April 13, 2000, issue of Nature, titled "Delaying the onset of Huntington's in mice."
Huntington's disease in humans is inherited in an autosomal dominant fashion, so that there is a 50 percent chance that each child will carry the defective gene. Tragically, the onset of symptoms is usually in the 40s and 50s, after the person has already had children. Children of sufferers then are faced with the decision of whether to find out if they have inherited the disease, knowing that if they test positive there is no treatment.
The genetic defect was characterized in 1993. A group of collaborating researchers, led by Gill Bates, of United Medical and Dental Schools in London, found that the gene responsible for Huntington's encodes a protein called huntingtin. Its function is not known.
Exon 1 of the huntingtin gene contains a sequence of CAG trinucleotide repeats. In healthy individuals, the number of CAG repeats is up to 35, while in people who have inherited the disease, the number is 37 and over. CAG codes for the amino acid glutamine. When this polyglutamine sequence is too long, the protein becomes insoluble and starts to aggregate and precipitate in cells.
Bates and colleagues managed to insert exon 1 of the human huntingtin gene plus its promoter into the mouse genome, generating transgenic mice that develop brain histology typical of Huntington's disease, as well as behavioural features similar to those experienced by human sufferers. For example, they develop a tremor and other movement abnormalities.
Van Dellen and his colleagues decided to investigate the effect on these mice of "environmental enrichment." They took 30 mice, 16 of which carried exon 1 of the human huntingtin transgene. All the mice were housed in large cages and provided with normal food and bedding. Fifteen mice were then allocated to a "normal" environment and 15 to a "stimulating" environment. Those in the environmentally enriched group were given cardboard, paper and plastic objects, which were changed every two days, from the age of 4 weeks.
Tests carried out between 19 and 22 weeks of age showed that mice from the enriched group preferred to spend their time exploring such objects rather than remain in a standard environment. The researchers also evaluated the time of onset of disease symptoms.
To test the motor coordination of the mice, the animals were provided with a "turning task." This involved placing them at the end of a suspended horizontal wooden rod, rather as if "walking the plank." A normal mouse placed facing outward can turn around on the rod and walk back to a position of safety. Mice with poor coordination of movement would fall off, however.
In this study, only one of the transgenic mice (14 percent) that had been kept in the enriched environment fell off the rod by 22 weeks, a significant improvement compared to the transgenic mice kept in the normal environment (p<0.000001). There was a significant delay in the onset of other signs of disease, too.
Van Dellen and his colleagues went on to examine the brains of the animals, at 22 weeks of age. They measured the volume of the striatum, which is the part of the brain governing coordination of movement, and the first to be affected in Huntington's disease. The volume of the striatum was slightly larger in the transgenic mice that had been kept in the enriched environment than in those kept in the normal environment, but this difference was not significant.
When the researchers went on to measure the volume of the area of brain surrounding the striatum, they found that this "peristriatal cerebral volume" was 13 percent larger in the environmentally enriched transgenic mice than in the transgenic mice kept in the normal environment. This difference was statistically significant (p<0.05). There was no difference in this volume between wild-type mice kept in the two different environments.
The Nature paper concludes: "These results suggest that environmental enrichment delays the degenerative loss of cerebral volume in [these transgenic] mice and that the corticostriatal pathway plays a role in the pathogenesis of [Huntington's disease]."
Van Dellen told BioWorld International that the study implies that the part of the brain most affected by environmental enrichment includes the area outside the striatum, but closely connected to it. He added: "Studies which focus purely on the striatum are missing a large piece of the puzzle in Huntington's disease. Our work shows that the connections between the cortex and the striatum are very significant. It is likely that changes in the cortex are responsible for delaying the onset of the disease in the environmentally enriched group, as well as changes in the striatum itself."
This conclusion ties in, he said, with previous findings by another group, at Harvard University in Cambridge, Mass. This team discovered that the receptors in the striatum that are downregulated in Huntington's disease are those which are present on nerve cells emanating from the cortex.
Van Dellen and his colleagues now are embarking on a collaboration with the Harvard group to examine which genes are upregulated in the brain during the process of environmental enrichment.
"If we know that environmental enrichment upregulates gene A, then if we find a method of upregulating gene A, then hopefully this would delay the onset of Huntington9s disease, van Dellen said. "This approach will allow us to pursue a more rational development of pharmacological therapies. It may open a new range of pharmacological compounds that previously were not thought to be significant in this disease."