The ALS Association Funds Mouse Mutagenesis Project

November 12, 2004

The ALS Association (ALSA) today announced funding for an ALSA-initiated project to be carried out at the Jackson Laboratories in Bar Harbor, Maine.   Investigators Gregory Cox, Ph.D., Associate Staff Scientist, and Kevin Seburn, Ph.D., Research Scientist, are specifically seeking the genes that modify disease onset in mouse models of ALS.

“The current proposal builds on the resources generated over the past four years and continues the collaborative effort to find more and better models for the study of motor neuron disease, the investigators said.   Prior ALSA funding has yielded a gait analysis system revealing defects in motor performance in mice early on. ALSA support has also produced several new strains of mice modeling human ALS. Two of these strains change disease onset and progression in SOD1 mutant mice. The Jackson Lab investigators will look specifically for the modifying genes that are speeding up or slowing the disease induced by the SOD1 mutation, G93A. It is likely that just a few genes control the difference in lifespan between these two strains of mice. The genetic diversity between the two strains will allow unique combinations of polymorphic loci to be analyzed and genetically mapped, said Cox and Seburn, thus providing insights into the mechanisms of disease and possible genetic targets for intervention.”

“The goal is to find genes that tell us about disease mechanisms, commented ALSA Lucie Bruijn, Ph.D. science director and vice president. This grant is crucial to finding important genes in the pathway of mutant SOD1 toxicity that will give new insights towards designing therapies.”

ALSA had partnered with the NIH on a mouse mutagenesis program at Jackson Lab (click here for more information.) This prior funding has led to a new approach to finding genes that alter disease progression in the SOD1 mutant mice. In the first project, the yield of mutants relevant to ALS was limited, in part due to the delayed onset typical of ALS. Looking for a disease that starts late in life is expensive, time consuming and more importantly technically challenging to generate the appropriate mouse lines because once a phenotype is detected, the mice can no longer be bred. In the initial effort, most of the new mouse models carry mutants showing motor defects due to glitches in development. Renewed effort will now seek further, unique mutations that alter the already available SOD1 mutant mice bearing the G93A change.

New mutations will be randomly introduced into genes in the G93A mice, using a chemical mutagen. Researchers will seek to identify those mice that survive longer or die earlier. This approach may lead researchers to new genes involved in the disease pathway and hence new drug targets.

The ALSA-funded gait analysis system has revealed altered walking on a treadmill, by eight weeks of age for a new, congenic strain, the B6 SOD1 mice. Cox and Seburn will seek genes that change the lifespan of these mice. The investigators will also seek to genetically manipulate the ALS2 knockout mouse. No overt effect is apparent in mice who do not express the ALS2 gene, a gene associated with juvenile onset ALS in people. Cox and Seburn will try to introduce new mutations that will produce a recognizable change in mice bearing the ALS2 mutation. Chemically induced mutations might sensitize mice to the lack of the ALS2 gene product. Once a visibly affected mouse results, the investigators can sift out those with early or late onset and screen for genetic modifiers of that difference.

This is a very exciting study by leading investigators in the field of mouse genetics and has great potential to find new genes linked to ALS, added Bruijn said.