Axonal mRNA translation in neurological disorders

Abstract

It is increasingly recognized that local protein synthesis (LPS) contributes to fundamental aspects of axon biology, in both developing and mature neurons. Mutations in RNA-binding proteins (RBPs), as central players in LPS, and other proteins affecting RNA localization and translation are associated with a range of neurological disorders, suggesting disruption of LPS may be of pathological significance. In this review, we substantiate this hypothesis by examining the link between LPS and key axonal processes, and the implicated pathophysiological consequences of dysregulated LPS. First, we describe how the length and autonomy of axons result in an exceptional reliance on LPS. We next discuss the roles of LPS in maintaining axonal structural and functional polarity and axonal trafficking. We then consider how LPS facilitates the establishment of neuronal connectivity through regulation of axonal branching and pruning, how it mediates axonal survival into adulthood and its involvement in neuronal stress responses.

RNA Localization and Local Translation in Glia in Neurological and Neurodegenerative Diseases: Lessons from Neurons

“…Interestingly, Fmrp mRNA itself is also localized to and translated within dendrites [ 79 ]. Moreover, FMRP is expressed in developing and mature axons [ 80 , 81 , 82 , 83 ] where its loss alters synaptic connectivity in both Drosophila and mouse FXS models [ 3 ].…”

“…Although once considered heretical, mechanisms of localizing RNAs have proven to be highly prevalent and conserved in eukaryotes [ 2 ]. Additionally, translation of localized mRNAs, also known as local protein synthesis, is increasingly being recognized as a crucial mechanism that contributes to the physiology of the nervous system (NS) [ 3 ].…”

“…Malfunctioning of RBPs, deregulation of the translation machinery, changes in the local mRNA repertoire or failure of molecular motors to accurately sort mRNAs to their target compartment can contribute to the disruption of protein homeostasis at a subcellular level. These alterations on the local proteome lead to cellular dysfunction, which in the case of the NS translate into neurological and neurodegenerative diseases [ 3 , 6 ].…”

Peripheral neuropathy linked mRNA export factor GANP reshapes gene regulation in human motor neurons

“…Pathogenic variants in the mRNA export factor GLE1 also underlie a motor neuron disease, suggesting that motor neurons are vulnerable to inefficient mRNA export [10,21,39]. Reduced mRNA availability could have a major effect on local protein synthesis in axons, which is now recognized to be important for axon maintenance and synaptic function [34].…”

The emerging RNA-centric world of neurobiology

“…Indeed, several studies have documented compartment-specific regulation of protein synthesis underlying synapse-specific forms of long-term memory storage [3,4]. In a comprehensive overview of axonal translation, Christine Holt and colleagues provide a big picture view of protein synthesis in axons, as well as of the underlying mechanisms and their implications for neurological and neurodevelopmental disorders [5]. Importantly, this review highlights the challenges of assessing the role of compartmentalized translation, as well as the recent development of subcellular multiomic methodologies to study axonal translation.…”