Korea Brain Research Institute, Research Division, Daegu 700-010, Korea.
Exp Neurobiol. 2015 Mar;24(1):1-7. doi: 10.5607/en.2015.24.1.1. Epub 2014 Dec 17.
ALS is a fatal adult-onset motor neuron disease. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3~5 years of disease onset due to respiratory failure. The major pathological hallmark of ALS is abnormal accumulation of protein inclusions containing TDP-43, FUS or SOD1 protein. Moreover, the focality of clinical onset and regional spreading of neurodegeneration are typical features of ALS. These clinical data indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation with pathogenic prion proteins. In vitro and cell line experimental evidence suggests that SOD1, TDP-43 and FUS form insoluble fibrillar aggregates. Notably, these protein fibrillar aggregates can act as seeds to trigger the aggregation of native counterparts. Collectively, a self-propagation mechanism similar to prion replication and spreading may underlie the pathology of ALS. In this review, we will briefly summarize recent evidence to support the prion-like properties of major ALS-associated proteins and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism.
肌萎缩侧索硬化症（ALS）是一种致命的成年起病的运动神经元疾病。在 ALS 患者中，大脑皮层、脑干和脊髓中的运动神经元逐渐退化，大多数 ALS 患者在发病后 3~5 年内因呼吸衰竭而死亡。ALS 的主要病理学特征是含有 TDP-43、FUS 或 SOD1 蛋白的异常蛋白包涵体的积累。此外，ALS 的临床发病局灶性和神经退行性病变的区域性扩散是其典型特征。这些临床数据表明，ALS 中的神经退行性变是一个有序的传播过程，似乎与致病性朊病毒蛋白的种子自我传播特征具有相似性。体外和细胞系实验证据表明，SOD1、TDP-43 和 FUS 形成不溶性纤维状聚集物。值得注意的是，这些蛋白质纤维状聚集物可以作为种子触发天然蛋白的聚集。总的来说，类似于朊病毒复制和传播的自我传播机制可能是 ALS 病理学的基础。在这篇综述中，我们将简要总结最近的证据，以支持主要的 ALS 相关蛋白的类朊病毒特性，并讨论基于类朊病毒机制的 ALS 可能的治疗策略。
