Department of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093.
Proc Natl Acad Sci U S A. 2024 Nov 12;121(46):e2317860121. doi: 10.1073/pnas.2317860121. Epub 2024 Nov 4.
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.
二十多年前，研究人员在患有肌萎缩侧索硬化症（ALS）、阿尔茨海默病、帕金森病和其他神经退行性疾病的尸检患者中报告了 RNA 氧化水平的升高。有趣的是，并非所有细胞类型和转录本都受到同等程度的氧化。此外，研究表明 RNA 氧化是一种早期现象，这表明氧化 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，但此后该领域似乎已经停滞不前。我们认为，这是由于模拟这些疾病的技术存在缺陷所致，这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、它们对 RNA 加工有何影响以及因此它们在疾病发生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，并提出了如何结合和利用 iPSC 衍生疾病建模、蛋白质组学和测序技术的进步来回答新的和几十年前的问题的方法。
