ORIGINAL PAPER Dietary Lipid Unsaturation Influences Survival and Oxidative Modifications of an Amyotrophic Lateral Sclerosis Model in a Gender-Specific Manner Daniel Cacabelos • Victoria Ayala • Omar Ramı ´rez-Nunez • Ana Belen Granado-Serrano • Jordi Boada • Jose C. E. Serrano • Rosanna Cabre ´ • Gisela Nadal-Rey • Maria Josep Bellmunt • Isidro Ferrer • Reinald Pamplona • Manuel Portero-Otin Received: 1 January 2014 / Accepted: 20 June 2014 / Published online: 1 July 2014 Ó Springer Science+Business Media New York 2014 Abstract The implication of lipid peroxidation in neu- rodegenerative diseases, including amyotrophic lateral sclerosis (ALS) derive from high abundance of peroxida- tion-prone polyunsaturated fatty acids in central nervous system and its relatively low antioxidant content. In the present work, we evaluated the effect of dietary changes aimed to modify fatty acid tissular composition in survival, disease onset, protein, and DNA oxidative modifications in the hSODG93A transgenic mice, a model of this motor neuron disease. Both survival and clinical evolution is dependent on dietary fatty acid unsaturation and gender, with high unsaturated diet, leading to loss of the disease- sparing effect of feminine gender. This was associated with significant increases in protein carbonyl and glycoxidative modifications as well as non-nuclear 8-oxo-dG, a marker of mitochondrial DNA oxidation. Comparison of these data with cH2AX immunostaining, a marker of DNA damage response, suggests that the highly unsaturated diet-blunted mitochondrial–nuclear free radical dependent crosstalk, since increased 8-oxo-dG was not correlated with increased DNA damage response. Paradoxically, the highly unsatu- rated diet led to lower peroxidizability but higher anti- inflammatory indexes. To sum up, our results demonstrate that high polyunsaturated fatty acid content in diets may accelerate the disease in this model. Further, these results reinforce the need for adequately defining gender as a relevant factor in ALS models, as well as to use structurally characterized markers for oxidative damage assessment in neurodegeneration. Keywords Oxidative stress Á Polyunsaturated fatty acid Á DNA repair response Á Gender dimorphism Á Lipid peroxidation Introduction Amyotrophic lateral sclerosis (ALS, OMIM #105400) is a neurodegenerative, motor neuron-specific disease that causes death within 2–5 years after diagnosis. ALS spo- radic forms account for most of the cases and despite much effort have been done, their causes remain unclear. How- ever, familial forms of the disease (fALS) provide a valuable tool for the development of animal models to gain insight into disease mechanisms and therapy design, especially at preclinical stages. A breakthrough point in this line was the discovery by Rosen (1993), showing that mutations in Cu/ZnSOD were a primary cause for ALS. Since then, multiple mutations on Cu/ZnSOD (more than Electronic supplementary material The online version of this article (doi:10.1007/s12017-014-8317-7) contains supplementary material, which is available to authorized users. D. Cacabelos Á V. Ayala Á O. Ramı ´rez-Nunez Á A. B. Granado-Serrano Á J. Boada Á J. C. E. Serrano Á R. Cabre ´ Á G. Nadal-Rey Á M. J. Bellmunt Á R. Pamplona Á M. Portero-Otin (&) NUTREN-Nutrigenomics, Institut de Recerca Biome `dica de Lleida-Universitat de Lleida, Av. Rovira Roure 80, 25198 Lleida, Spain e-mail: manuel.portero@mex.udl.cat I. Ferrer Institut de Neuropatologia, Hospital Universitari de Bellvitge - IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, Spain I. Ferrer CIBERNED (Centro de Investigacio ´n Biome ´dica en Red de Enfermedades Neurodegenerativas), Instituto Carlos III, Spanish Ministry of Health, Madrid, Spain 123 Neuromol Med (2014) 16:669–685 DOI 10.1007/s12017-014-8317-7