Characterization of the Contribution of Genetic Background and Gender to Disease Progression in the SOD1 G93A Mouse Model of Amyotrophic Lateral Sclerosis: A Meta-Analysis

J Neuromuscul Dis. 2015;2(2):137-150. doi: 10.3233/JND-140068. Epub 2015 Jun 4.


Background: The SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS) is the most frequently used model to examine ALS pathophysiology. There is a lack of homogeneity in usage of the SOD1 G93A mouse, including differences in genetic background and gender, which could confound the field's results.

Objective: In an analysis of 97 studies, we characterized the ALS progression for the high transgene copy control SOD1 G93A mouse on the basis of disease onset, overall lifespan, and disease duration for male and female mice on the B6SJL and C57BL/6J genetic backgrounds and quantified magnitudes of differences between groups.

Methods: Mean age at onset, onset assessment measure, disease duration, and overall lifespan data from each study were extracted and statistically modeled as the response of linear regression with the sex and genetic background factored as predictors. Additional examination was performed on differing experimental onset and endpoint assessment measures.

Results: C57BL/6 background mice show delayed onset of symptoms, increased lifespan, and an extended disease duration compared to their sex-matched B6SJL counterparts. Female B6SJL generally experience extended lifespan and delayed onset compared to their male counterparts, while female mice on the C57BL/6 background show delayed onset but no difference in survival compared to their male counterparts. Finally, different experimental protocols (tremor, rotarod, etc.) for onset determination result in notably different onset means.

Conclusions: Overall, the observed effect of sex on disease endpoints was smaller than that which can be attributed to the genetic background. The often-reported increase in lifespan for female mice was observed only for mice on the B6SJL background, implicating a strain-dependent effect of sex on disease progression that manifests despite identical mutant SOD1 expression.

Keywords: ALS; Amyotrophic Lateral Sclerosis; Lou Gehrig’s disease; forelimb tremor; hindlimb tremor; motoneuron disease; rotarod; transgenic mice.