Over two decades ago, increased levels of RNA oxidation were reported in postmortem patients with ALS, Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. Interestingly, not all cell types and transcripts were equally oxidized. Furthermore, it was shown that RNA oxidation is an early phenomenon, altogether indicating that oxidative RNA damage could be a driver, and not a consequence, of disease. Despite all these exciting observations, the field appears to have stagnated since then. We argue that this is a consequence of the shortcomings of technologies to model these diseases, limiting our understanding of which transcripts are being oxidized, which RNA-binding proteins are interacting with these RNAs, what their implications are in RNA processing, and as a result, what their potential role is in disease onset and progression. Here, we discuss the limits of previous technologies and propose ways by which advancements in iPSC-derived disease modeling, proteomics, and sequencing technologies can be combined and leveraged to answer new and decades-old questions.

中文翻译：

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绘制神经退行性病变中氧化 RNA 损伤的未来：用新工具重新思考现状


二十多年前，据报道，患有 ALS、阿尔茨海默氏症、帕金森氏症和其他神经退行性疾病的死后患者的 RNA 氧化水平升高。有趣的是，并非所有细胞类型和转录本都被同等氧化。此外，研究表明 RNA 氧化是一种早期现象，总之表明氧化性 RNA 损伤可能是疾病的驱动因素，而不是结果。尽管有这些令人兴奋的观察结果，但从那时起，该领域似乎停滞不前。我们认为，这是模拟这些疾病的技术缺陷的结果，限制了我们对哪些转录本被氧化、哪些 RNA 结合蛋白与这些 RNA 相互作用、它们在 RNA 加工中的作用以及它们在疾病发作和进展中的潜在作用的理解。在这里，我们讨论了以前技术的局限性，并提出了将 iPSC 衍生疾病建模、蛋白质组学和测序技术的进步结合起来的方法，以回答新的和几十年来的问题。