Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University Yokohama, Japan.
Front Cell Neurosci. 2014 Mar 18;8:83. doi: 10.3389/fncel.2014.00083. eCollection 2014.
Abnormal accumulation of protein inclusions in motor neurons has been known as a major pathological change in amyotrophic lateral sclerosis (ALS). Increasing numbers of proteins including mutant Cu, Zn-superoxide dismutase (SOD1) have been identified as constituents of pathological inclusions in a form of insoluble fibrillar aggregates. Notably, protein fibrillar aggregates exhibit a self-perpetuating property, which can convert a soluble native protein into insoluble fibrillar aggregates. Such "seeding reaction" of protein fibrils can accelerate the aggregation significantly and would contribute to the spread of inclusion pathologies from an affected cell to its neighboring cells in neurodegenerative diseases. In ALS, a pathological change first occurs at the site of disease onset and then propagates throughout the affected tissues in a time-dependent manner; therefore, it can be assumed that seeded aggregation may be the key factor of disease progression in ALS. In this mini review, we will briefly summarize recent studies on possible roles of a seeded aggregation of SOD1 in pathomechanism of ALS.
在运动神经元中异常聚集蛋白包涵体已被认为是肌萎缩侧索硬化症 (ALS) 的主要病理变化。越来越多的蛋白质，包括突变的铜锌超氧化物歧化酶（SOD1），已被确定为病理性包涵体的组成部分，其形式为不溶性纤维状聚集物。值得注意的是，蛋白质纤维状聚集物表现出自维持特性，它可以将可溶性天然蛋白质转化为不溶性纤维状聚集物。这种蛋白质纤维的“接种反应”可以显著加速聚集，并有助于包涵体病变从受影响的细胞传播到神经退行性疾病中的邻近细胞。在 ALS 中，病理变化首先发生在疾病起始部位，然后以时间依赖性方式在受影响的组织中传播；因此，可以假设接种聚集可能是 ALS 疾病进展的关键因素。在这篇小综述中，我们将简要总结 SOD1 接种聚集在 ALS 发病机制中的可能作用的最新研究。
