Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis
Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis
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DOI：
10.1073/pnas.1308421110
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发表时间：
2013-06-25
影响因子：
11.1
通讯作者：
Shihabuddin, Lamya S.
中科院分区：
文献类型：
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作者：
Dodge, James C.;Treleaven, Christopher M.;Shihabuddin, Lamya S.
代谢紊乱是肌萎缩侧索硬化症(ALS)病程的重要调节因子。我们在这里报告了ALS的家族性小鼠模型(过度表达铜/锌超氧化物歧化酶1基因的G93A突变的转基因小鼠)进入进行性酸中毒状态，这与有利于脂肪分解的几种代谢(激素)变化有关。对H+浓度的主要决定因素(即强离子差异和强离子间隙)的广泛研究表明，酸中毒还部分归因于未知阴离子的存在。与避免病理性酸中毒的代偿反应一致，ALS小鼠在中枢神经系统和内脏组织中糖原积累增加。糖原的改变与溶酶体和中性α-葡萄糖苷酶活性的波动有关。在ALS尸检患者的脊髓组织样本中也发现了与疾病相关的糖原、葡萄糖和α-葡萄糖苷酶活性的变化。总而言之，这些数据为ALS的发病机制以及药物开发的潜在靶点提供了见解。
Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation of the Cu/Zn superoxide dismutase 1 gene) of ALS enters a progressive state of acidosis that is associated with several metabolic (hormonal) alternations that favor lipolysis. Extensive investigation of the major determinants of H+ concentration (i.e., the strong ion difference and the strong ion gap) suggests that acidosis is also due in part to the presence of an unknown anion. Consistent with a compensatory response to avert pathological acidosis, ALS mice harbor increased accumulation of glycogen in CNS and visceral tissues. The altered glycogen is associated with fluctuations in lysosomal and neutral a-glucosidase activities. Disease-related changes in glycogen, glucose, and a-glucosidase activity are also found in spinal cord tissue samples of autopsied patients with ALS. Collectively, these data provide insights into the pathogenesis of ALS as well as potential targets for drug development.