Translation stalling in neurons: a critical mechanism for timely protein delivery to distal cellular processes

Neurons require local protein synthesis at synapses to control their proteome in response to local inputs. Work over the past two decades has revealed that neurons can use a specialized mechanism to transfer mRNAs and ribosomes to local sites in addition to canonical mechanisms used in many cell types. Neurons initiate translation on the ribosomes in the cellular soma, pause the process, and then package these stalled ribosomes into structures known as ‘neuronal RNA granules’ that are transported to synapses. This review provides an overview of recent studies that characterize these ribosomes/granules biochemically and structurally. These studies provide novel insights into the unique and specialized characteristics of neuronal ribosomes that facilitate this distinct transport mechanism. Many questions remain, including the influence of mRNA sequences on the stalling process and how ribosomes in the granules avoid the physiological responses that, in other cells, recycle ribosomal subunits upon stalling. Many neurodevelopmental disorders, such as autism and intellectual disability, occur when local translation is disrupted in neurons. Understanding mechanisms underlying the stalling of neuronal ribosomes, their transport to processes, and their reactivation may enable novel therapies for neurodevelopmental diseases.