Senataxin, A Novel Helicase at the Interface of RNA Transcriptome Regulation and Neurobiology: From Normal Function to Pathological Roles in Motor Neuron Disease and Cerebellar Degeneration
Senataxin, A Novel Helicase at the Interface of RNA Transcriptome Regulation and Neurobiology: From Normal Function to Pathological Roles in Motor Neuron Disease and Cerebellar Degeneration
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DOI：
10.1007/978-3-319-89689-2_10
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发表时间：
2018-01-01
期刊：
影响因子：
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通讯作者：
La Spada, Albert R.
中科院分区：
文献类型：
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作者：
Bennett, Craig L.;La Spada, Albert R.
Senataxin（SETX）是一种DNA-RNA解旋酶，其C-末端区域与酵母蛋白Sen 1 p的解旋酶结构域具有同源性。遗传学发现已经确定了SETX对神经功能的重要性，因为SETX基因中的隐性突变导致共济失调伴眼动性失用2型（AOA 2）（OMIM：606002），这是第三种最常见的隐性共济失调形式，仅次于弗里德赖希共济失调和共济失调-毛细血管扩张症。此外，罕见的显性SETX突变导致肌萎缩侧索硬化症（ALS）的青少年发病形式，称为ALS 4。SETX执行许多RNA调节功能，包括维持RNA转录组稳态。在过去的十年中，改变的RNA调节和异常的RNA结合蛋白功能已经成为运动神经元疾病发病机制的中心主题，有证据表明散发性ALS疾病病理学可能与家族性ALS中发现的分子病理学重叠。与其他与ALS相关的RNA加工蛋白一样，SETX功能获得性运动神经元毒性的基础仍然不明确。对酵母Sen 1 p和哺乳动物SETX蛋白的研究揭示了一系列重要的RNA调节功能，包括R环的分解以允许转录终止和RNA剪接。越来越多的证据表明，SETX可能代表了一个重要的遗传修饰位点散发性ALS。在细胞周期中，SETX在S/G（2）细胞周期过渡期的核灶中被发现，并可能在复制体和转录机制之间的碰撞位点发挥作用。虽然我们还不知道哪些SETX活动对神经退行性变最关键，但我们对SETX功能的不断了解无疑不仅对于理解SETX在ALS和共济失调疾病发病机制中的作用至关重要，而且对于描绘细胞中基本重要分子过程的机制生物学也至关重要。
Senataxin (SETX) is a DNA-RNA helicase whose C-terminal region shows homology to the helicase domain of the yeast protein Sen1p. Genetic discoveries have established the importance of SETX for neural function, as recessive mutations in the SETX gene cause Ataxia with Oculomotor Apraxia type 2 (AOA2) (OMIM: 606002), which is the third most common form of recessive ataxia, after Friedreich's ataxia and Ataxia-Telangiectasia. In addition, rare, dominant SETX mutations cause a juvenile-onset form of Amyotrophic Lateral Sclerosis (ALS), known as ALS4. SETX performs a number of RNA regulatory functions, including maintaining RNA transcriptome homeostasis. Over the last decade, altered RNA regulation and aberrant RNA-binding protein function have emerged as a central theme in motor neuron disease pathogenesis, with evidence suggesting that sporadic ALS disease pathology may overlap with the molecular pathology uncovered in familial ALS. Like other RNA processing proteins linked to ALS, the basis for SETX gain-of-function motor neuron toxicity remains ill-defined. Studies of yeast Sen1p and mammalian SETX protein have revealed a range of important RNA regulatory functions, including resolution of R-loops to permit transcription termination, and RNA splicing. Growing evidence suggests that SETX may represent an important genetic modifier locus for sporadic ALS. In cycling cells, SETX is found at nuclear foci during the S/G(2) cell-cycle transition phase, and may function at sites of collision between components of the replisome and transcription machinery. While we do not yet know which SETX activities are most critical to neurodegeneration, our evolving understanding of SETX function will undoubtedly be crucial for not only understanding the role of SETX in ALS and ataxia disease pathogenesis, but also for delineating the mechanistic biology of fundamentally important molecular processes in the cell.