title: Early and gender-specific differences in spinal cord mitochondrial function and oxidative stress markers in a mouse model of ALS.
abstract: BACKGROUND
  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.
  
  
  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 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.
authors.affiliation: The Metabolic Pathophysiology Research Group, Deparment Experimental Medicine, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL- IRBLleida), Avda Rovira Roure, 80, E-25198, Lleida, Spain. Daniel.cacabelos@mex.udl.cat.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cacabelos
authors.affiliation: The Metabolic Pathophysiology Research Group, Deparment Experimental Medicine, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL- IRBLleida), Avda Rovira Roure, 80, E-25198, Lleida, Spain. omar.ramirez78@mex.udl.cat.
authors.forename: Omar
authors.initials: O
authors.lastname: Ramírez-Núñez
authors.affiliation: The Metabolic Pathophysiology Research Group, Deparment Experimental Medicine, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL- IRBLleida), Avda Rovira Roure, 80, E-25198, Lleida, Spain. anabgs@mex.udl.cat.
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Granado-Serrano
authors.affiliation: The Metabolic Pathophysiology Research Group, Deparment Experimental Medicine, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL- IRBLleida), Avda Rovira Roure, 80, E-25198, Lleida, Spain. pascual.tc92@gmail.com.
authors.forename: Pascual
authors.initials: P
authors.lastname: Torres
authors.affiliation: The Metabolic Pathophysiology Research Group, Deparment Experimental Medicine, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL- IRBLleida), Avda Rovira Roure, 80, E-25198, Lleida, Spain. victoria.ayala@mex.udl.cat.
authors.forename: Victòria
authors.initials: V
authors.lastname: Ayala
authors.affiliation: The Metabolic Pathophysiology Research Group, Deparment Experimental Medicine, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL- IRBLleida), Avda Rovira Roure, 80, E-25198, Lleida, Spain. pro100vicky@hotmail.com.
authors.forename: Victoria
authors.initials: V
authors.lastname: Moiseeva
authors.affiliation: The Neurology Service, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, c/La Feixa Llarga, S/N 08908 Hospitalet de Llobregat, Barcelona, Spain. 30058mpp@gmail.com.
authors.forename: Mònica
authors.initials: M
authors.lastname: Povedano
authors.affiliation: Institut de Neuropatologia, Hospital Universitari de Bellvitge - IDIBELL, Universitat de Barcelona, and CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Instituto Carlos III, Spanish Ministry of Health, Spain. L'Hospitalet de Llobregat, c/La Feixa Llarga, S/N 08908 Hospitalet de Llobregat, Barcelona, Spain. 8082ifa@gmail.com.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: The Metabolic Pathophysiology Research Group, Deparment Experimental Medicine, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL- IRBLleida), Avda Rovira Roure, 80, E-25198, Lleida, Spain. reinald.pamplona@mex.udl.cat.
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.affiliation: The Metabolic Pathophysiology Research Group, Deparment Experimental Medicine, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL- IRBLleida), Avda Rovira Roure, 80, E-25198, Lleida, Spain. manuel.portero@mex.udl.cat.
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otin
authors.affiliation: The Metabolic Pathophysiology Research Group, Deparment Experimental Medicine, University of Lleida-Institute for Research in Biomedicine of Lleida (UdL- IRBLleida), Avda Rovira Roure, 80, E-25198, Lleida, Spain. jboada@mex.udl.cat.
authors.forename: Jordi
authors.initials: J
authors.lastname: Boada
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009046:Motor Neurons / Q000648:ultrastructure*; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D010101:Oxygen Consumption / Q000235:genetics; D012737:Sex Factors; D013116:Spinal Cord / Q000473:pathology* / Q000648:ultrastructure; D013482:Superoxide Dismutase
chemical_list: D005227:Fatty Acids; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase