Mouse genetic model for spongiform brain diseases

Some mice with a genetic mutation for mahogany-colored coats also develop spongiform degeneration of brain tissue, similar to mad cow disease. Because of this oddity, the mice could be valuable animal models for human disorders, such as Parkinson’s and Alzheimer’s diseases, according to geneticists at Cornell and Stanford universities.

The surprising discovery in a mouse strain known to geneticists since the 1960s is reported in the latest issue of the journal Science (Jan. 31, 2003) by Teresa M. Gunn, Gregory S. Barsh and their collaborators as “Spongiform Degeneration in mahoganoid Mutant Mice.”

“Just don’t call them mad mice,” pleads Gunn, an assistant professor of genetics in Cornell’s College of Veterinary Medicine who began the research in Barsh’s laboratory at Stanford. “We do see the same kind of tissue degeneration — with fluid-filled vacuoles, or holes, where the gray matter should be — in BSE cattle with bovine spongiform encephalopathy and in these mutant mice. But the mice don’t have the same motor coordination problems as mad cows, and the condition is not lethal.”

Rather, the mutant mice exhibit little more than a slight tremor when they begin to move, they live a normal life span for their species and are able to reproduce, Gunn says. Nor did the investigators find evidence of misshapen prion proteins (the cause of spongiform encephalopathies such as mad cow and mad elk diseases) in the mice, although they did see damage to the myelin sheaths around nerve cells. Among other distinguishing characteristics of the mutant mice are curly whiskers and slightly curly body hair, as well as the habit of clasping their hind feet together when lifted off the ground. Normal mice tend to splay their legs straight out when they are elevated, Gunn explains.

Furthermore, this form of neurodegeneration is not known to be contagious, Gunn says, noting: “A cat that eats a mahoganoid mutant mouse — should one escape from the laboratory — would not get spongiform encephalopathy.”

The researchers were looking for effects that might be linked to mutations in pigmentation genes. They knew that a loss of function in the so-called Mahogunin gene causes a partial reduction in the amount of yellow pigment, so that the mice were left with only small patches of yellow hair on mostly black bodies. But they were surprised to learn that a complete loss of function in that gene produced all-black mice with brain neurodegeneration. Linkages between unusual pigmentation and neural defects are not unheard of in the animal world, Gunn adds, citing predominantly white dogs, such as Dalmatians, that sometimes are deaf.

As an animal model, the mahoganoid mutant mice probably will not be useful to study spongiform encephalopathies like mad cow disease, Gunn believes, because rogue prions are not the cause of the mouse condition. But as an example of defective ubiquitination — a protein-related process involved in many neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases — the mahogany-colored mice with spongy brains could have real value, according to the Cornell scientist.

And the mutant mouse probably isn’t patentable because it has a naturally occurring defect that the researchers did not create and because the mice already are commercially available. However, Gunn suggests, further work with the gene responsible for the neurodegenerative condition might result in patent applications.

Gunn credits Cornell undergraduate student Aaron F. Jolly for his research assistance in the study. Jolly is one of eight co-authors of the Science report. The study was supported, in part, by grants from the National Institutes of Health and the American Heart Association.