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

Abstract

BackgroundThe 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.ObjectiveIn 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.MethodsMean 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.ResultsC57BL/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.ConclusionsOverall, 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.

An Assessment of Possible Neuropathology and Clinical Relationships in 46 Sporadic Amyotrophic Lateral Sclerosis Patient Autopsies

“…Also, as has been previously shown, we found that gender does not have a clear impact on clinical patient survival [19], despite reports that female transgenic SOD1 mice tend to have a longer disease duration [e.g. 26, 27]. Further study in larger patient populations is necessary to establish the potential role of gender on clinical ALS parameters.…”

Androgen receptor antagonism accelerates disease onset in the SOD1G93A mouse model of amyotrophic lateral sclerosis

“…This was confirmed in the current study, as we show that flutamide can accelerate disease onset and motor deficits in male mice, with concomitant exacerbation in myofibre atrophy. Castration in SOD1 G93A mice has shown to both induce muscle hypotrophy (Yoo & Ko, 2012) and have no effect on clinical parameters (Aggarwal et al, 2014) and may reflect influences from the genetic background of mice on the transgene (Pfohl et al, 2015). To date, castration has consistently failed to modify disease onset or survival in male SOD1 G93A mice (Aggarwal et al, 2014;Sheean et al, 2015;Yoo & Ko, 2012).…”

“…While this evidence is largely based on cohorts of sporadic ALS patients, accounting for 90% of the disease, other evidence suggests a male predominance in familial ALS patients with SOD1 mutations (Kim et al, ) and C9orf72 repeat expansions (Rooney et al, ). Sex‐related effects are reproduced in the SOD1 G93A mouse model of ALS with males showing earlier disease onset with decreased survival, depending on the background strain (Pfohl, Halicek, & Mitchell, ). Furthermore, TDP‐43 A315T male mice have earlier disease onset and death, compared to females (Hatzipetros et al, ).…”

“…Sex-related effects are reproduced in the SOD1 G93A mouse model of ALS with males showing earlier disease onset with decreased survival, depending on the background strain (Pfohl, Halicek, & Mitchell, 2015).…”

Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis

“…Genetic background affects the disease progression of ALS (Mancuso et al, 2012). A recent meta-analysis showed that SOD1 G93A mice bred on the C57BL/6J background show delayed symptom onset (111.4 AE 2.86 days) and an increased life span (144.4 AE 1.97 days) compared to those of their B6SJL counterparts (onset = 99.86 AE 2.161 days; life span = 127.39 AE 1.46 days) (Pfohl et al, 2015). Therefore, based on the findings of previous studies evaluating the disease stages of SOD1 G93A mice bred on a C57BL/6J background (Beers et al, 2008) and our own observations, we established the following age limits for each disease stage of the transgenic animals: 9 weeks, presymptomatic stage; 15 weeks, progressive stage; and 21 weeks, end stage.…”