Nonsense-mediated mRNA decay in neuronal physiology and neurodegeneration

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.

Automated summary

The processes of mRNA export and translation play important roles in gene expression regulation in eukaryotic cells, particularly in highly polarised cells like neurons. Nonsense-mediated mRNA decay (NMD) is a translation-dependent quality control process that regulates gene expression in the nervous system and is involved in neurodevelopment, learning, and memory formation. Dysregulation of NMD has been linked to various neurodevelopmental and neurodegenerative disorders. This article discusses the role of NMD and mRNA translation in neuronal functions, with a focus on their involvement in the molecular pathogenesis of neurodegeneration. Additionally, it explores the therapeutic potential and challenges of targeting these processes in neurological diseases that currently lack effective treatments.