Laboratory of Experimental Neurosciences, University of Southern Santa Catarina, 88137-270, Palhoca, Santa Catarina, Brazil.
Mol Neurobiol. 2013 Aug;48(1):71-7. doi: 10.1007/s12035-013-8415-9. Epub 2013 Mar 19.
Congenital muscular dystrophies present mutated gene in the LARGE mice model and it is characterized by an abnormal glycosylation of α-dystroglycan (α-DG), strongly implicated as having a causative role in the development of central nervous system abnormalities such as cognitive impairment seen in patients. However, the pathophysiology of the brain involvement remains unclear. Therefore, the objective of this study is to evaluate the oxidative damage and energetic metabolism in the brain tissue as well as cognitive involvement in the LARGE((myd)) mice model of muscular dystrophy. With this aim, we used adult homozygous, heterozygous, and wild-type mice that were divided into two groups: behavior and biochemical analyses. In summary, it was observed that homozygous mice presented impairment to the habituation and avoidance memory tasks; low levels of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex, hippocampus, cortex and cerebellum; increased lipid peroxidation in the prefrontal cortex, hippocampus, striatum, and cerebellum; an increase of protein peroxidation in the prefrontal cortex, hippocampus, striatum, cerebellum, and cortex; a decrease of complex I activity in the prefrontal cortex and cerebellum; a decrease of complex II activity in the prefrontal cortex and cerebellum; a decrease of complex IV activity in the prefrontal cortex and cerebellum; an increase in the cortex; and an increase of creatine kinase activity in the striatum and cerebellum. This study shows the first evidence that abnormal glycosylation of α-DG may be affecting BDNF levels, oxidative particles, and energetic metabolism thus contributing to the memory storage and restoring process.
先天性肌肉萎缩症在 LARGE 小鼠模型中表现出突变基因，其特征是α-肌营养不良聚糖（α-DG）的异常糖基化，强烈暗示其在中枢神经系统异常的发展中起因果作用，如患者中所见的认知障碍。然而，大脑受累的病理生理学仍不清楚。因此，本研究的目的是评估肌肉营养不良 LARGE((myd))小鼠模型中脑组织的氧化损伤和能量代谢以及认知功能障碍。为此，我们使用成年纯合子、杂合子和野生型小鼠，将其分为两组：行为和生化分析。总之，观察到纯合子小鼠在习惯化和回避记忆任务中表现出障碍；大脑源性神经营养因子（BDNF）在前额叶皮质、海马体、皮质和小脑中的水平降低；在前额叶皮质、海马体、纹状体和小脑中的脂质过氧化增加；在前额叶皮质、海马体、纹状体、小脑和皮质中的蛋白质过氧化增加；在前额叶皮质和小脑中的复合物 I 活性降低；在前额叶皮质和小脑中的复合物 II 活性降低；在前额叶皮质和小脑中的复合物 IV 活性降低；在前额叶皮质中的增加；在前额叶皮质和小脑中的 creatine kinase 活性增加。本研究首次表明，α-DG 的异常糖基化可能会影响 BDNF 水平、氧化颗粒和能量代谢，从而有助于记忆存储和恢复过程。
