基因背景和性别对肌萎缩侧索硬化症SOD1 G93A小鼠模型疾病进展影响的特征分析：一项荟萃分析

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.

作者信息

Pfohl Stephen R, Halicek Martin T, Mitchell Cassie S

机构信息

Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA.

出版信息

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.

背景

超氧化物歧化酶1（SOD1）基因G93A突变的肌萎缩侧索硬化症（ALS）小鼠模型是研究ALS病理生理学最常用的模型。SOD1 G93A小鼠的使用缺乏一致性，包括遗传背景和性别的差异，这可能会混淆该领域的研究结果。

目的

在对97项研究的分析中，我们基于疾病发作、总体寿命和疾病持续时间，对B6SJL和C57BL/6J遗传背景的雄性和雌性高转基因拷贝对照SOD1 G93A小鼠的ALS进展进行了表征，并量化了组间差异的大小。

方法

提取每项研究的平均发病年龄、发病评估指标、疾病持续时间和总体寿命数据，并将其作为线性回归的响应进行统计建模，将性别和遗传背景作为预测因子。对不同的实验发病和终点评估指标进行了额外检查。

结果

与性别匹配的B6SJL小鼠相比，C57BL/6背景的小鼠症状发作延迟、寿命延长且疾病持续时间延长。雌性B6SJL小鼠通常比雄性对应小鼠寿命延长且发病延迟，而C57BL/6背景的雌性小鼠发病延迟，但与雄性对应小鼠相比生存无差异。最后，用于确定发病的不同实验方案（震颤、转棒试验等）导致显著不同的发病均值。