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.

Keywords: Neurological disorders; RNA-binding protein; axon branching; axon survival; axonal trafficking; local protein synthesis; neuronal stress.

Figure 1.

Selective GO terms and KEGG pathways in most abundant axonal transcripts, ribosome-bound mRNAs and nascent proteins

Figure 2.

Disease-associated genes enriched in axonal transcriptomes and translatomes

Figure 3.

Mechanisms to sustain axonal transport related to LPS. Neurofilaments and membrane-associated periodic skeleton regulate axon structure (upper segment); microtubule and motor protein-based active transport maintains cargo trafficking (middle segment); modulation of axonal RBP, RNA and organelle density controls local macromolecular crowdedness (lower segment). Perturbation of these processes can result in defective axonal trafficking, as indicated by pink axon segments

Figure 4.

Selected contributions by LPS to synaptic survival and adaptability. LPS in the presynaptic terminal contributes to a range of processes important for neuronal maintenance, including I. survival signalling, II. remodelling of cytoskeletal elements, and III. maintenance of mitochondria