Background

Amyotrophic lateral sclerosis (ALS) is among the most common of the motor neuron diseases, and arguably the most devastating. During the course of this fatal neurodegenerative disorder, motor neurons undergo progressive degeneration. The currently best-understood animal models of ALS are based on the over-expression of mutant isoforms of Cu/Zn superoxide dismutase 1 (SOD1); these indicate that there is a perturbation in metal homeostasis with disease progression. Copper metabolism in particular is affected in the central nervous system (CNS) and muscle tissue.

Methods

This present study assessed previously published and newly gathered concentrations of transition metals (Cu, Zn, Fe and Se) in CNS (brain and spinal cord) and non-CNS (liver, intestine, heart and muscle) tissues from transgenic mice over-expressing the G93A mutant SOD1 isoform (SOD1^G93A), transgenic mice over-expressing wildtype SOD1 (SOD1^WT) and non-transgenic controls.

Results

Cu accumulates in non-CNS tissues at pre-symptomatic stages in SOD1^G93A tissues. This accumulation represents a potentially pathological feature that cannot solely be explained by the over-expression of mSOD1. As a result of the lack of Cu uptake into the CNS there may be a deficiency of Cu for the over-expressed mutant SOD1 in these tissues. Elevated Cu concentrations in muscle tissue also preceded the onset of symptoms and were found to be pathological and not be the result of SOD1 over-expression.

Conclusions

It is hypothesized that the observed Cu accumulations may represent a pathologic feature of ALS, which may actively contribute to axonal retraction leading to muscular denervation, and possibly significantly contributing to disease pathology. Therefore, it is proposed that the toxic-gain-of-function and dying-back hypotheses to explain the molecular drivers of ALS may not be separate, individual processes; rather our data suggests that they are parallel processes.

中文翻译：

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评估肌萎缩性侧索硬化症的SOD1 ^G93A小鼠模型中的金属浓度及其在肌肉神经支配中的潜在作用，尤其是针对肌肉组织

背景

肌萎缩性侧索硬化症（ALS）是最常见的运动神经元疾病之一，并且可以说是最具破坏性的。在这种致命的神经退行性疾病的过程中，运动神经元经历进行性变性。目前最容易理解的ALS动物模型基于Cu / Zn超氧化物歧化酶1（SOD1）突变体同工型的过表达；这些表明金属稳态会随着疾病的进展而受到干扰。铜代谢尤其会影响中枢神经系统（CNS）和肌肉组织。

方法

本研究评估了过表达的转基因小鼠中枢神经系统（大脑和脊髓）和非中枢神经系统（肝，肠，心脏和肌肉）组织中先前发表和新收集的过渡金属（铜，锌，铁和硒）的浓度G93A突变型SOD1亚型（SOD1 ^G93A），过表达野生型SOD1（SOD1 ^WT）的转基因小鼠和非转基因对照。

结果

Cu在SOD1 ^G93A组织的症状发生前的非CNS组织中积累。这种积累代表了潜在的病理特征，不能仅通过mSOD1的过度表达来解释。由于缺乏铜吸收到中枢神经系统中，这些组织中过表达的突变型SOD1可能缺乏铜。肌肉组织中的铜浓度升高也早于症状发作，并且被发现是病理性的，而不是SOD1过表达的结果。

结论

假设观察到的Cu积累可能代表ALS的病理特征，它可能积极地导致轴突收缩，从而导致肌肉神经支配，并可能显着地导致疾病病理。因此，建议将有毒-增益-的-功能和垂死-回假说来解释ALS的分子司机可以不是分离的，单独的过程; 相反，我们的数据表明它们是并行的过程。