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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a gender bias towards major prevalence in male individuals
As a second estimation of disease progression, stride length was measured with paw print analysis and in this case the onset of clinical weakness was quantified by determining the age at which shortening of the stride length was lower than 40 % for two consecutive measures
Overexpression of HSOD1-G93A in Neuro 2A cells leads to a loss in complex I function which can be prevented by estradiol Higher estrogen level in females could explain the gender-related differences, since these hormones have mitochondrial effects [57, 58]. To evaluate whether these could explain gender differences in mitochondrial function in G93A mice, we studied the effects of estradiol preincubation (10 days) in N2A cells expressing either wild type hSOD1 or G93A-mutated hSOD1 (both containing enhanced green fluorescent protein (EGFP) to control transfection, which achieved 80–90 % efficiency (Additional file 2: Figure S5)
Summary
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a gender bias towards major prevalence in male individuals. Individual factors could help to explain the great clinical heterogeneity of this disease, with similar mutations leading to markedly clinically different disease forms. Among these factors, gender differences in many neurodegenerative diseases are observed across epidemiologic studies, pathophysiology, and treatments [8, 9]. Lending further support to the greater occurrence of familial ALS in men than in women, data extracted from the ALSoD website (http://alsod.iop.kcl.ac.uk) revealed a 1.5 male/female ratio for most mendelian ALS-related mutant genes, including SOD1. It has been reported that gender can account for variations in the course of disease in familial ALS [13]
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