The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London (UCL), Queen Square, WC1N 3BG London, UK.
Trends Neurosci. 2023 Oct;46(10):879-892. doi: 10.1016/j.tins.2023.07.001. Epub 2023 Aug 3.
The processes of mRNA export from the nucleus and subsequent mRNA translation in the cytoplasm are of particular relevance in eukaryotic cells. In highly polarised cells such as neurons, finely-tuned molecular regulation of these processes serves to safeguard the spatiotemporal fidelity of gene expression. Nonsense-mediated mRNA decay (NMD) is a cytoplasmic translation-dependent quality control process that regulates gene expression in a wide range of scenarios in the nervous system, including neurodevelopment, learning, and memory formation. Moreover, NMD dysregulation has been implicated in a broad range of neurodevelopmental and neurodegenerative disorders. We discuss how NMD and related aspects of mRNA translation regulate key neuronal functions and, in particular, we focus on evidence implicating these processes in the molecular pathogenesis of neurodegeneration. Finally, we discuss the therapeutic potential and challenges of targeting mRNA translation and NMD across the spectrum of largely untreatable neurological diseases.
mRNA 从细胞核输出和随后在细胞质中翻译的过程在真核细胞中尤为重要。在高度极化的细胞（如神经元）中，这些过程的精细分子调控有助于保障基因表达的时空保真度。无意义介导的 mRNA 降解（NMD）是一种依赖于细胞质翻译的质量控制过程，它在神经系统的广泛场景中调节基因表达，包括神经发育、学习和记忆形成。此外，NMD 失调与广泛的神经发育和神经退行性疾病有关。我们讨论了 NMD 和相关的 mRNA 翻译如何调节关键的神经元功能，特别是我们关注这些过程在神经退行性变分子发病机制中的证据。最后，我们讨论了靶向 mRNA 翻译和 NMD 在广泛的、基本上无法治疗的神经疾病中的治疗潜力和挑战。
