Mapping the future of oxidative RNA damage in neurodegeneration: Rethinking the status quo with new tools

• 成果类型: Article
• 署名作者: Wheeler, Hailey B.; Madrigal, Assael A.; Chaim, Isaac A.
• 署名单位: University of California System; University of California San Diego
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13646
• DOI: 10.1073/pnas.2317860121
• 发表日期: 2024-11-12
• 关键词: familial alzheimers-disease; parkinsons-disease; messenger-rna; dna-damage; ribosomal-rna; amyloid-beta; cellular rna; mouse model; early event; abasic rna

摘要

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.