Enge T Gabriel, Ecroyd Heath, Jolley Dianne F, Yerbury Justin J, Dosseto Anthony
Wollongong Isotope Geochronology Laboratory, School of Earth and Environmental Sciences, University of Wollongong, Wollongong, NSW 2522, Australia.
Illawarra Health and Medical Research Institute and School of Biological Sciences, University of Wollongong, Australia.
Metallomics. 2017 Feb 22;9(2):161-174. doi: 10.1039/c6mt00270f.
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease, which involves progressive motor neuron degeneration in the central nervous system (CNS). The G93A SOD1 mouse model simulates one of the most common causes of familial ALS through the overexpression of a mutated form of the human gene encoding copper/zinc superoxide dismutase (SOD1). Transition metals, particularly Cu and Zn, have been shown to behave abnormally in the disease context and have been hypothesized to contribute to and potentially trigger the disease. In this study, concentrations of Cu, Zn and Fe, as well as Cu isotope ratios were assessed in keystone tissues of ALS, including the brain, spinal cord, muscle and whole blood, from transgenic mutant SOD1 mice and non-transgenic controls. While no consistent Cu isotope signal was found to be related to the disease state, concentrations of Cu, Zn and Fe were significantly elevated in muscle tissue of the transgenic mice, even at pre-symptomatic time points. In brain and muscle tissue, in both animal groups, a time-dependent Cu isotope signal was observed. We hypothesize that the early and significant elevation in metal concentration in muscle tissue from SOD1 transgenic mice could facilitate the development of ALS, without affecting the overall signal from well-buffered CNS tissues. Ageing may be recorded isotopically as a shift from a neonatal Cu pool as inherited from the mother, through dietary Cu and recycling processes.
肌萎缩侧索硬化症（ALS）是一种运动神经元疾病，涉及中枢神经系统（CNS）中运动神经元的进行性退化。G93A SOD1小鼠模型通过过度表达编码铜/锌超氧化物歧化酶（SOD1）的人类基因突变形式，模拟了家族性ALS最常见的病因之一。过渡金属，特别是铜和锌，已被证明在疾病背景下表现异常，并被假设为促成并可能引发该疾病。在本研究中，对转基因突变SOD1小鼠和非转基因对照的ALS关键组织（包括脑、脊髓、肌肉和全血）中的铜、锌和铁浓度以及铜同位素比率进行了评估。虽然未发现一致的铜同位素信号与疾病状态相关，但转基因小鼠肌肉组织中的铜、锌和铁浓度显著升高，即使在症状前时间点也是如此。在两个动物组的脑和肌肉组织中，均观察到了随时间变化的铜同位素信号。我们假设，SOD1转基因小鼠肌肉组织中金属浓度的早期显著升高可能促进ALS的发展，而不会影响缓冲良好的中枢神经系统组织的整体信号。衰老可能通过从母亲遗传的新生儿铜库，经饮食铜和循环过程，以同位素方式记录为一种转变。
