From the ALS Association:

In a published report in the May 2005 issue of Muscle and Nerve, researchers at The Jackson Laboratory funded by The ALS Association (ALSA) demonstrate that treadmill gait falters long before overt symptoms appear, in mice that have symptoms similar to ALS. The early and subtle loss of motor function should help scientists to target crucial aspects of ALS much sooner in the disease process using mice that model the disease.

The treadmill test of mouse gait is simple, rapid, and measured by computer. As such, it can be used as a screening tool for therapeutics, the scientists write.

Patients with ALS often are not diagnosed until problems are well apparent. New treatments may provide the best impact if they are applied as early in the course of the disorder as possible. “We need to find therapeutic targets to not only arrest disease, but to prevent irreversible damage from developing,” said Kevin Seburn, an investigator in the study.

ALSA Science Director Lucie Bruijn emphasized the value of the gait analysis system for researchers. “It is already being used not only for the mouse but the ALS rat and is being considered for use in other neurodegenerative diseases.”

Seburn and colleagues used mice bearing a mutation analogous to one responsible for some inherited cases of human ALS. These mice show similar symptoms to ALS. The mutation is in the enzyme copper zinc superoxide dismutase 1 (SOD1).

Jackson researchers and colleagues pioneered the gait analysis system as part of the ALSA funded program (see http://www.alsa.org/news/article.cfm?id=547). To test the system, the investigators used a different strain of ALS mice than previously available, with less genetic variability. The resulting mice display ALS-like changes about a month later compared to the prior SOD1 mice.

Despite the later onset, the researchers can see the earliest signs of disease in these mice ever reported in a mouse model of ALS, thanks to the gait analysis system. They write, “We describe the earliest functional deficits (8 weeks) that have been reported for SOD1 transgenic mice, at least to our knowledge.” Even earlier changes may be evident if younger ALS mice are tested in the treadmill assay, the scientists write.

As part of the ALSA funded project, Jackson Laboratory investigators contracted with Mouse Specifics Inc. and Clever Sys Inc to produce the gait analysis system. The treadmill test reveals gait change as early as eight weeks after birth. At this time, a longer stride for the mutant mice is evident, by analysis of video showing their foot placement while walking on the treadmill. Also, control mice improve their performance after a single session on the treadmill at that age, but the ALS mutant mice do not.

The scientists point out that the time course for treadmill problems parallels the appearance of the first signs of damage at the nerve muscle junction in other ALS mice. The early loss of connections between nerve and muscle precedes actual loss of the motor neurons. Overt signs of disease, such as tremor in the hind limb, appear weeks later in the mice, starting at 20 weeks of age.

Bruijn said the findings provide important characterization of the new strain of mouse that should serve to model ALS in the lab.