TDP-43 in neurodegeneration and cancer: Decoding the mechanism of mRNA localization and translation

The localization and translation of mRNAs play crucial roles in maintaining cellular phenotype and function, with RNA-binding protein (RBP) contributing significantly to these processes. TAR DNA-binding protein of 43 kDa (TDP-43) is an RNA/DNA-binding protein that is primarily localized in the nucleus, where it performs essential functions in pre-mRNA splicing, mRNA transport, and the stabilization and localized translation of mRNA. Its mis-localization from the cytoplasm, as well as mutations, protein misfolding, and posttranslational modifications, is closely linked to a reduction in its RNA-binding ability. This functional impairment is implicated in the initiation and progression of neurodegenerative diseases and cancer. In this review, we begin with a retrospective analysis of the molecular mechanism by which distinct domains of TDP-43 contribute to the initiation and progression of disease, particularly because its overexpression in tumors significantly influences disease progression. We subsequently elucidate the classical mechanisms of mRNA localization and translation, while clarifying the role of TDP-43 in these processes. Finally, we summarize the mechanisms by which TDP-43 facilitates the formation of ribonucleoprotein particles and this protein's involvement in mRNA localization and translation, as well as its associated molecular pathways. In conclusion, this review highlights the critical roles of TDP-43 and subsequent therapeutic strategies for treatment of neurodegenerative diseases and tumors. • Illustrate the pathogenic mechanisms of distinct domains of TDP-43. • Retrospectively examine the role of TDP-43 ribonucleoprotein particles in the formation of liquid-liquid phase separation. • Underscore the importance of mRNA localization and translation of TDP-43. • Discuss the application potential of TDP-43 in the contexts of neurodegeneration and cancer.