Early and gender-specific differences in spinal cord mitochondrial function and oxidative stress markers in a mouse model of ALS
Early and gender-specific differences in spinal cord mitochondrial function and oxidative stress markers in a mouse model of ALS
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DOI：
10.1186/s40478-015-0271-6
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发表时间：
2016-01-13
影响因子：
7.1
通讯作者：
Boada, Jordi
中科院分区：
文献类型：
--
作者：
Cacabelos, Daniel;Ramirez-Nunez, Omar;Boada, Jordi
简介：肌萎缩性侧索硬化症（ALS）是一种运动神经元疾病，以男性为主。一些数据表明氧化应激和线粒体功能障碍参与其发病机制，尽管性别之间的差异尚未得到评估。因此，我们分析了G93A突变的Cu， Zn超氧化物歧化酶（hSOD1-G93A）转基因小鼠和过表达hSOD1-G93A的Neuro2A（N2A）细胞的线粒体氧化代谢特征，以及线粒体链复合体酶活性和蛋白质表达、脂质谱和蛋白质氧化应激标志物。结果和结论：我们的研究结果表明，转基因小鼠中hSOD1-G93A的过表达降低了线粒体氧化磷酸化的效率，位于复合物I，揭示了雌性相对于雄性的时间延迟，这与蛋白质氧化损伤的选择标记平行增加有关。此外，雌性在30天时表现出较高水平的二十二碳六烯酸脂肪酸谱。机制研究表明，hSOD1-G93A在N2A细胞中的过表达降低了复合物I的功能，这一缺陷可以通过17 -雌二醇预处理来预防。综上所述，与雄性小鼠相比，als相关的SOD1突变导致雌性小鼠线粒体功能障碍延迟，部分原因是前者的雌激素水平较高。这项研究对于进一步了解不同程度的脊髓线粒体功能障碍是否可能是ALS的疾病调节剂具有重要意义。
Introduction: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a gender bias towards major prevalence in male individuals. Several data suggest the involvement of oxidative stress and mitochondrial dysfunction in its pathogenesis, though differences between genders have not been evaluated. For this reason, we analysed features of mitochondrial oxidative metabolism, as well as mitochondrial chain complex enzyme activities and protein expression, lipid profile, and protein oxidative stress markers, in the Cu, Zn superoxide dismutase with the G93A mutation (hSOD1-G93A)- transgenic mice and Neuro2A(N2A) cells overexpressing hSOD1-G93A.Results and Conclusions: Our results show that overexpression of hSOD1-G93A in transgenic mice decreased efficiency of mitochondrial oxidative phosphorylation, located at complex I, revealing a temporal delay in females with respect to males associated with a parallel increase in selected markers of protein oxidative damage. Further, females exhibit a fatty acid profile with higher levels of docosahexaenoic acid at 30 days. Mechanistic studies showed that hSOD1-G93A overexpression in N2A cells reduced complex I function, a defect prevented by 17 beta-estradiol pretreatment. In conclusion, ALS-associated SOD1 mutation leads to delayed mitochondrial dysfunction in female mice in comparison with males, in part attributable to the higher oestrogen levels of the former. This study is important in the effort to further understanding of whether different degrees of spinal cord mitochondrial dysfunction could be disease modifiers in ALS.