B6.SOD1G93A transgenic mice, bred on a congenic C57BL/6 background, offer a compelling alternative to the commonly used SOD1(*G93A)1Gur mice. They exhibit a slightly slower progression of the amyotrophic lateral sclerosis (ALS)-specific phenotype compared to the original strain, which is conventionally bred on a mixed C57BL/6xSJL background. The slower disease course offers an extended window for therapeutic interventions, potentially leading to new treatment strategies.
Electromyographic (EMG) assessment of B6.SOD1G93A mice reveals a sustained reduction in compound muscle action potential (CMAP; Figure 1A) and motor unit action potential (MUAP; Figure 1B) compared to ntg littermates. Consistent with EMG observations, B6.SOD1G93A mice demonstrate a progressive decline in muscle strength, as evidenced in the grip strength test (Figure 1C) and impaired performance in the wire hanging test (Figure 1D).
Figure 1: Longitudinal EMG recording and muscle strength analysis. Electromyographic recordings by CMAP (A) as well MUAP (B) measurement. Muscle strength measurement by analysis of maximal forelimb force in the grip strength test (C) and hanging time in the wire hanging test (D). All analyses were performed in B6.SOD1G93A mice compared to ntg littermates at the age of 8, 14, and 20 weeks. Two-way ANOVA with genotype as main factor, followed by Bonferroni’s post hoc test. Mean ± SEM. *p<0.05; ***p <0.001. n= 16 per group.
Furthermore, B6.SOD1G93A mice exhibit evident neurodegeneration at the age of 14 weeks as shown by increased plasma neurofilament light chain (NF-L) levels (Figure 2A) which progressively worsen over time resulting in a striking neurodegeneration at 20 weeks. In addition, autophagy marker p62 levels are increased at 20 weeks of age in the cervical, thoracic, and lumbar part of the spinal cord.
Figure 2: Neuronal loss and autophagy in B6SJL.SOD1-G93A mice. A: Quantification of NF-L in the plasma of B6.SOD1G93A mice compared to ntg littermates at the age of 8, 14, and 20 weeks. B: Quantification of the autophagy marker p62 in the cervical, thoracic, and lumbar spinal cord evaluated as area under the curve (AUC) in 20 weeks old B6.SOD1G93A mice and ntg littermates. A-D: Two-way ANOVA with Bonferroni post hoc test. Mean + SEM. n = 4-8 per group. *p<0.05; **p<0.01 ***p<0.001.
The progressive motor deficits and neurodegeneration observed in B6.SOD1G93A mice replicate the human ALS phenotype, making these mice a valuable model to investigate underlying ALS pathological mechanisms. The observed slower progression offers an advantageous extended window for pharmacological interventions. Supplementing behavioral assessments with additional longitudinal measures, such as repeated EMG assessment and NF-L analysis of in vivo plasma samples, enables a more nuanced and sensitive evaluation of drug candidates aimed at combatting ALS.
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