Cacabelos Daniel, Ayala Victoria, Ramírez-Nunez Omar, Granado-Serrano Ana Belen, Boada Jordi, Serrano Jose C E, Cabré Rosanna, Nadal-Rey Gisela, Bellmunt Maria Josep, Ferrer Isidro, Pamplona Reinald, Portero-Otin Manuel
NUTREN-Nutrigenomics, Institut de Recerca Biomèdica de Lleida-Universitat de Lleida, Av. Rovira Roure 80, 25198, Lleida, Spain.
Neuromolecular Med. 2014 Dec;16(4):669-85. doi: 10.1007/s12017-014-8317-7. Epub 2014 Jul 1.
The implication of lipid peroxidation in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) derive from high abundance of peroxidation-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 γH2AX 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 unsaturated 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.
脂质过氧化在包括肌萎缩侧索硬化症（ALS）在内的神经退行性疾病中的影响源于中枢神经系统中大量易于发生过氧化的多不饱和脂肪酸及其相对较低的抗氧化剂含量。在本研究中，我们评估了旨在改变脂肪酸组织组成的饮食变化对hSODG93A转基因小鼠（这种运动神经元疾病的模型）的生存、疾病发作、蛋白质和DNA氧化修饰的影响。生存和临床进展均取决于饮食脂肪酸的不饱和度和性别，高不饱和饮食会导致女性性别对疾病的保护作用丧失。这与蛋白质羰基化和糖氧化修饰以及线粒体DNA氧化标志物非核8-氧代脱氧鸟苷的显著增加有关。将这些数据与DNA损伤反应标志物γH2AX免疫染色进行比较表明，高不饱和饮食削弱了线粒体-细胞核自由基依赖性串扰，因为增加的8-氧代脱氧鸟苷与增加的DNA损伤反应不相关。矛盾的是，高不饱和饮食导致较低的过氧化能力但较高的抗炎指数。总之，我们的结果表明，饮食中高含量的多不饱和脂肪酸可能会加速该模型中的疾病进展。此外，这些结果强化了将性别作为ALS模型中的一个相关因素进行充分定义的必要性，以及使用结构特征明确的标志物进行神经退行性变中氧化损伤评估的必要性。
