MRC Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
Mamm Genome. 2011 Aug;22(7-8):420-48. doi: 10.1007/s00335-011-9339-1. Epub 2011 Jun 26.
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure. Breakthroughs in understanding ALS pathogenesis came with the discovery of dominant mutations in the superoxide dismutase 1 gene (SOD1) and other genes, including the gene encoding transactivating response element DNA binding protein-43 (TDP-43). This has led to the creation of animal models to further our understanding of the disease and identify a number of ALS-causing mechanisms, including mitochondrial dysfunction, protein misfolding and aggregation, oxidative damage, neuronal excitotoxicity, non-cell autonomous effects and neuroinflammation, axonal transport defects, neurotrophin depletion, effects from extracellular mutant SOD1, and aberrant RNA processing. Here we summarise the SOD1 and TDP-43 animal models created to date, report on recent findings supporting the potential mechanisms of ALS pathogenesis, and correlate this understanding with current developments in the clinic.
肌萎缩侧索硬化症（ALS）是一种致命的运动神经元疾病，目前尚无治愈方法。随着超氧化物歧化酶 1 基因（SOD1）和其他基因（包括编码反式激活反应元件 DNA 结合蛋白 43（TDP-43）的基因）中的显性突变的发现，对 ALS 发病机制的理解取得了突破。这导致创建了动物模型，以进一步了解该疾病并确定许多 ALS 致病机制，包括线粒体功能障碍、蛋白质错误折叠和聚集、氧化损伤、神经元兴奋毒性、非细胞自主效应和神经炎症、轴突运输缺陷、神经营养因子耗竭、细胞外突变 SOD1 的影响以及异常的 RNA 处理。在这里，我们总结了迄今为止创建的 SOD1 和 TDP-43 动物模型，报告了支持 ALS 发病机制潜在机制的最新发现，并将这种理解与临床的最新进展相关联。
