The Trail of Axonal Protein Synthesis: Origins and Current Functional Landscapes

Local protein synthesis (LPS) in axons is now recognized as a physiological process, participating both in the maintenance of axonal function and diverse plastic phenomena. In the last decades of the 20th century, the existence and function of axonal LPS were topics of significant debate. Very early, axonal LPS was thought not to occur at all and was later accepted to play roles only during development or in response to specific conditions. However, compelling evidence supports its essential and pervasive role in axonal function in the mature nervous system. Remarkably, in the last five decades, Uruguayan neuroscientists have contributed significantly to demonstrating axonal LPS by studying motor and sensory axons of the peripheral nervous system of mammals, as well as giant axons of the squid and the Mauthner cell of fish. For LPS to occur, a highly regulated transport system must deliver the necessary macromolecules, such as mRNAs and ribosomes. This review discusses key findings related to the localization and abundance of axonal mRNAs and their translation levels, both in basal states and in response to physiological processes, such as learning and memory consolidation, as well as neurodevelopmental and neurodegenerative disorders, including Alzheimer's disease, autism spectrum disorder, and axonal injury. Moreover, we discuss the current understanding of axonal ribosomes, from their localization to the potential roles of locally translated ribosomal proteins, in the context of emerging research that highlights the regulatory roles of the ribosome in translation. Lastly, we address the main challenges and open questions for future studies.