肌萎缩侧索硬化症(ALS)是一种进行性、无法治愈的神经退行性疾病,其特征是运动神经元降解导致肌肉损伤,失败,和死亡。Senataxin,由SETX基因编码,是一种人类解旋酶蛋白,其突变与ALS发病有关,特别是在其青少年ALS4形式。使用Senataxin的酵母同源物Sen1作为研究模型,提示Senataxin的N端与RNA聚合酶II相互作用,而其C端参与解旋酶活性。Senataxin大量参与转录调控,终止,和R循环分辨率,通过募集和与泛素蛋白连接酶SAN1和核糖核酸酶H(RNaseH)等酶的相互作用来实现。Senataxin还参与DNA损伤反应(DDR),主要与外泌体亚基Rrp45相互作用。Sen1突变E1597K,与Senataxin的L389S和R2136H功能获得突变一起,被证明会对蛋白质产生负面的结构和功能影响,从而导致WT功能的中断,运动神经元(MN)变性,以及ALS临床症状的表现。本文对Senataxin的结构和功能及其突变在ALS病理学中的作用进行了综述和总结,以期整理现有知识,为今后的研究提供参考。这篇综述中汇编的发现表明了senataxin及其突变作为未来ALS治疗/治愈发现目标的实验和治疗潜力,一些潜在的治疗途径也在综述中讨论。
Amyotrophic lateral sclerosis (ALS) is a progressive, uncurable neurodegenerative disorder characterized by the degradation of motor neurons leading to muscle impairment, failure, and death. Senataxin, encoded by the SETX gene, is a human helicase protein whose mutations have been linked with ALS onset, particularly in its juvenile ALS4 form. Using senataxin\'s yeast homolog
Sen1 as a model for study, it is suggested that senataxin\'s N-terminus interacts with RNA polymerase II, whilst its C-terminus engages in helicase activity. Senataxin is heavily involved in transcription regulation, termination, and R-loop resolution, enabled by recruitment and interactions with enzymes such as ubiquitin protein ligase SAN1 and ribonuclease H (RNase H). Senataxin also engages in DNA damage response (DDR), primarily interacting with the exosome subunit Rrp45. The
Sen1 mutation E1597K, alongside the L389S and R2136H gain-of-function mutations to senataxin, is shown to cause negative structural and thus functional effects to the protein, thus contributing to a disruption in WT functions, motor neuron (MN) degeneration, and the manifestation of ALS clinical symptoms. This review corroborates and summarizes published papers concerning the structure and function of senataxin as well as the effects of their mutations in ALS pathology in order to compile current knowledge and provide a reference for future research. The findings compiled in this review are indicative of the experimental and therapeutic potential of senataxin and its mutations as a target in future ALS treatment/cure discovery, with some potential therapeutic routes also being discussed in the review.