Abstract：
A complex interaction between genetic and external factors determines the development of amyotrophic lateral sclerosis (ALS). Epidemiological studies on large patient cohorts have suggested that ALS is a multi-step disease, as symptom onset occurs only after exposure to a sequence of risk factors. Although the exact nature of these determinants remains to be clarified, it seems clear that: (i) genetic mutations may be responsible for one or more of these steps; (ii) other risk factors are probably linked to environment and/or to lifestyle, and (iii) compensatory plastic changes taking place during the ALS etiopathogenesis probably affect the timing of onset and progression of disease. Current knowledge on ALS mechanisms and therapeutic targets, derives mainly from studies involving superoxide dismutase 1 (SOD1) transgenic mice; therefore, it would be fundamental to verify whether a multi-step disease concept can also be applied to these animal models. With this aim, a meta-analysis study has been performed using a collection of primary studies (n = 137), selected according to the following criteria: (1) the studies should employ SOD1 transgenic mice; (2) the studies should entail the presence of a disease-modifying experimental manipulation; (3) the studies should make use of Kaplan-Meier plots showing the distribution of symptom onset and lifespan. Then, using a subset of this study collection (n = 94), the effects of treatments on key molecular mechanisms, as well as on the onset and progression of disease have been analysed in a large population of mice. The results are consistent with a multi-step etiopathogenesis of disease in ALS mice (including two to six steps, depending on the particular SOD1 mutation), closely resembling that observed in patient cohorts, and revealed an interesting relationship between molecular mechanisms and disease manifestation. Thus, SOD1 mouse models may be considered of high predictive value to understand the determinants of disease onset and progression, as well as to identify targets for therapeutic interventions.
摘要：
遗传和外部因素之间的复杂相互作用决定了肌萎缩侧索硬化症（ALS）的发展。对大型患者队列的流行病学研究表明，ALS是一种多步骤疾病，因为只有在暴露于一系列危险因素后才会出现症状。尽管这些决定因素的确切性质仍有待澄清，似乎很清楚：（i）基因突变可能是一个或多个这些步骤的原因；（ii）其他风险因素可能与环境和/或生活方式有关，和（iii）在ALS病因发生过程中发生的代偿性可塑性变化可能会影响疾病的发作和进展时间。关于ALS机制和治疗靶点的最新知识，主要来自涉及超氧化物歧化酶1（SOD1）转基因小鼠的研究；因此，验证多步骤疾病概念是否也可以应用于这些动物模型将是至关重要的。为了这个目标,一项荟萃分析研究已经使用了一系列主要研究(n=137)，根据以下标准选择：（1）研究应使用SOD1转基因小鼠；（2）研究应需要进行疾病修饰实验操作；（3）研究应利用Kaplan-Meier图显示症状发作和寿命的分布。然后，使用这个研究集合的一个子集(n=94)，治疗对关键分子机制的影响，以及在大量小鼠中对疾病的发生和进展进行了分析。结果与ALS小鼠疾病的多步骤病因一致（包括两到六个步骤，取决于特定的SOD1突变)，与在患者队列中观察到的非常相似，并揭示了分子机制与疾病表现之间的有趣关系。因此，SOD1小鼠模型可能被认为具有很高的预测价值，以了解疾病发作和进展的决定因素。以及确定治疗干预的目标。
