Identification of early disease progression in an ALS rat model

Abstract

Transgenic rat models of amyotrophic lateral sclerosis (ALS) have recently been developed. Most assays of ALS-symptoms in these models monitor disease onset accurately, but do not identify individuals that will develop these symptoms before the motor deficits become apparent. Peak bodyweight has recently been shown to indicate affected individuals before motor deficits become apparent. However, it must be determined retrospectively due to weight fluctuation. Here, we report that exploratory activities detected by a photobeam activity system (PAS) and wire mesh ascending test can be used to detect slight motor deficits in the early phase of ALS. Thus, these tests may be used in addition to peak bodyweight to monitor early disease progression and to assay efficacy of new therapeutic interventions.

Fig. 1

Bodyweight measurements and time recordings on the wire mesh ascending test monitor pre-symptomatic disease progression. Bodyweight measurements (a) and wire mesh ascending test time recordings (b). wt, wild-type littermates (n=6). ALS, transgenic ALS rats (n=10). Male:female ratio 1:1 in both groups. Black arrows represent the average age of symptomatic disease onset (167.6 days). Dot line depicts the first value in ALS rats that is significantly different from wild-type littermates. *p < 0.05. ** p < 0.01. ***p < 0.001.

Fig. 2

Distance traveled and rearing capability, but not resting time, as measured in a Photobeam Activity System (PAS) identify pre-symptomatic motor deficits. Total distance traveled (a), total number of rearing events (b) and total resting time (c) as determined over a 15-min time period in a PAS. wt, wild-type littermates (n=6). ALS, transgenic ALS rats (n=10). Male: female ratio 1:1 in both groups. Black arrows represent the average age of symptomatic disease onset (167.6 days). Dot line depicts the first value in ALS rats that is significantly different from wild-type littermates. *p < 0.05. ** p < 0.01. ***p < 0.001. ⁺ 0.05 < p < 0.06.

Fig. 3

Transgenic ALS rats show a delayed symptomatic disease onset and lifespan compared to previous reports. Post-symptomatic disease progression based on a modified 5-point motor score (a). Kaplan-Meier survival curves depict the symptomatic disease onset (DO) and the end-stage (ES) (b). wt, wild-type littermates (n=6). ALS, transgenic ALS rats (n=10). Male: female ratio is 1:1 in both groups. Black arrow represents the average age of symptomatic disease onset (167.6 days). *p < 0.05. ** p < 0.01. ***p < 0.001. ⁺ p = 0.0703.