Neurons face an exceptional proteostasis challenge because their extreme polarization requires rapid proteome remodeling at distal axons and synapses. Rather than acting as separate systems, ribonucleoprotein granules and membranous organelles cooperate to form mobile translation platforms. This review proposes an RNA-binding protein-centered framework in which phase-separated condensates tether defined messenger RNA cohorts to organelle surfaces, creating organelle-anchored translation factories. These factories fall into three functional modules: long-range transport vehicles, local translation hubs, and stress-responsive nodes. Annexin A11 mediates lysosomal hitchhiking for long-range RNA delivery, whereas Rab7-positive late endosomes and FERRY-positive early endosomes couple translation to mitochondrial maintenance. In the axonal endoplasmic reticulum, p180 organizes microdomains for local synthesis, and SYNJ2BP anchors messenger RNAs to motile mitochondria to match local energy demand. During stress, mitochondria-endoplasmic reticulum contact sites prioritize translation of essential proteins. Disruption of these organelle–RNA-binding protein interfaces contributes to compartment-specific translational failure in amyotrophic lateral sclerosis and Charcot–Marie–Tooth disease, offering a framework for understanding neuronal proteostasis and therapeutic vulnerability.
https://doi.org/10.1093/procel/pwag026