Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part I, background and methods.
Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part I, background and methods.
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DOI：
10.1002/brb3.143
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发表时间：
2013-07
影响因子：
3.1
通讯作者：
Milligan C
中科院分区：
文献类型：
--
作者：
Vinsant S;Mansfield C;Jimenez-Moreno R;Del Gaizo Moore V;Yoshikawa M;Hampton TG;Prevette D;Caress J;Oppenheim RW;Milligan C
Charcot在1869年首次描述了肌萎缩侧索硬化症（ALS）;然而，其原因在很大程度上仍然未知，并且没有有效的长期治疗策略。ALS的第一个小鼠模型是在1993年鉴定出超氧化物歧化酶1（SOD 1）基因突变后开发的，因此我们对该疾病的病因和发病机制的大部分知识来自使用该动物模型进行的研究。尽管已经在突变SOD 1小鼠模型中进行了许多临床前试验，但结果令人失望，因为它们没有积极转化为临床试验。一种解释可能是，目前对发病机制何时何地开始的理解不足以准确指导临床前试验。这些早期事件的进一步表征可以提供对疾病发作的洞察，有助于发现症状前诊断疾病标志物，并确定新的治疗靶点。在这里，我们描述的理由，方法和方法，我们广泛的分析早期变化，包括超微结构检查的中央和外周成分的神经肌肉系统的SOD 1G 93 A小鼠和相关的这些变化与早期肌肉去神经支配，运动功能障碍，运动神经元死亡。我们还提供了一个讨论发表的工作，以审查什么是已知的关于早期病理学的SOD 1小鼠模型的ALS。这项工作的意义在于，我们同时检查了脊髓和外周神经肌肉系统的早期病理学，结果见配套文件（第二部分，结果和讨论）。我们的研究结果提供了证据，说明为什么在整个生命周期内对动物模型进行彻底的表征对于设计可能产生有意义结果的临床前试验的坚实基础至关重要。
Charcot first described amyotrophic lateral sclerosis (ALS) in 1869; however, its causes remain largely unknown and effective, long-term treatment strategies are not available. The first mouse model of ALS was developed after the identification of mutations in the superoxide dismutase 1 (SOD1) gene in 1993, and accordingly most of our knowledge of the etiology and pathogenesis of the disease comes from studies carried out using this animal model. Although numerous preclinical trials have been conducted in the mutant SOD1 mouse models, the results have been disappointing because they did not positively translate to clinical trials. One explanation may be that current understanding of when and where pathogenesis begins is insufficient to accurately guide preclinical trials. Further characterization of these early events may provide insight into disease onset, help in the discovery of presymptomatic diagnostic disease markers, and identify novel therapeutic targets. Here, we describe the rationale, approach, and methods for our extensive analysis of early changes that included an ultrastructural examination of central and peripheral components of the neuromuscular system in the SOD1G93A mouse and correlated these alterations with early muscle denervation, motor dysfunction, and motoneuron death. We also provide a discussion of published work to review what is known regarding early pathology in the SOD1 mouse model of ALS. The significance of this work is that we have examined early pathology simultaneously in both the spinal cord and peripheral neuromuscular system, and the results are presented in the companion paper (Part II, Results and Discussion). Our results provide evidence as to why a thorough characterization of animal models throughout the life span is critical for a strong foundation to design preclinical trials that may produce meaningful results.
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