Early and gender-specific differences in spinal cord mitochondrial function and oxidative stress markers in a mouse model of ALS

Abstract

IntroductionAmyotrophic 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 ConclusionsOur 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 17β-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0271-6) contains supplementary material, which is available to authorized users.

Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases

“…3 ; Menzies et al, 2002 ). In these models, several respiratory chain enzymes are defective, including complex I ( Cacabelos et al, 2016 ), but complex IV activity appears to be particularly susceptible, suggesting that this enzyme is targeted by mutant SOD1 ( Fig. 3 ).…”

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

“…Interestingly, previous studies identified sex-specific differences in mitochondrial function in SOD1 G93A mice that have been suggested to underlie female resilience in this line. Notably, female SOD1 G93A mice have increased activation of the mitochondrial unfolded protein response (UPRmt; Riar et al, 2017), reduced mitochondrial calcium accumulation (Kim et al, 2012) and improved preservation of Complex I function (Cacabelos et al, 2016). However, whether these sex-specific differences in mitochondrial function are mutation-or genetic-background-dependent remains to be determined.…”

ALS lymphoblastoid cell lines as a considerable model to understand disease mechanisms

“…Mitochondrial alterations represent a milestone in all the major neurodegenerative diseases, including ALS ( Smith et al, 2017 ; Lin and Beal, 2006 ). The evidence that mitochondria are impaired in ALS pathogenesis is clear from various studies involving cellular and animal models as well as ALS patients ( Tefera and Borges, 2017 ; Cacabelos et al, 2016 ; Allen et al, 2015 ). Defects in mitochondrial Ca 2+ buffering ability and in the activity of the electron transport protein complex were reported in the spinal cord of mutant SOD1 mice during the pre-symptomatic phase of the disease ( Abu-Hamad et al, 2017 ; Nalbandian et al, 2015 ; Kawamata and Manfredi, 2010 ).…”