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Popper, Bastian; Bürkle, Martina; Ciccopiedi, Giuliana; Marchioretto, Marta; Forné, Ignasi; Imhof, Axel; Straub, Tobias; Viero, Gabriella; Götz, Magdalena; Schieweck, Rico (2024): Ribosome inactivation regulates translation elongation in neurons. Journal of Biological Chemistry: 105648. ISSN 00219258

[thumbnail of PIIS0021925824000243.pdf] Published Article

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Cellular plasticity is crucial for adapting to ever-changing stimuli. As a result, cells consistently reshape their translatome, and, consequently, their proteome. The control of translational activity has been thoroughly examined at the stage of translation initiation. However, the regulation of ribosome speed in cells is widely unknown. In this study, we utilized a timed ribosome runoff approach, along with proteomics and transmission electron microscopy, to investigate global translation kinetics in cells. We found that ribosome speeds vary among various cell types, such as astrocytes, induced pluripotent human stem cells, human neural stem cells, and human and rat neurons. Of all cell types studied, mature cortical neurons exhibit the highest rate of translation. This finding is particularly remarkable because mature cortical neurons express the eukaryotic elongation factor 2 (eEF2) at lower levels than other cell types. Neurons solve this conundrum by inactivating a fraction of their ribosomes. As a result, the increase in eEF2 levels leads to a reduction of inactive ribosomes and an enhancement of active ones. Processes that alter the demand for active ribosomes, like neuronal excitation, cause increased inactivation of redundant ribosomes in an eEF2-dependent manner. Our data suggest a novel regulatory mechanism in which neurons dynamically inactivate ribosomes to facilitate translational remodeling. These findings have important implications for developmental brain disorders characterized by, among other things, aberrant translation.

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