Fine-Tuned Regulation of mRNA Translation and Transport by STAU2 Condensate Facilitates Neuronal Development and Plasticity

The double-stranded RNA-binding protein STAU2 plays an essential role in neural development and synaptic plasticity, assembling target mRNAs into ribonucleoprotein (RNP) granules to control their trafficking, localization, and local translation, though the detailed molecular mechanism remains elusive. Here, we show that STAU2 phase separates to form dynamic condensates in dendrites of hippocampal neurons, recruiting specific mRNAs to assemble mobile RNP granules that are transported distally along microtubules. These RNA-loaded STAU2 condensates undergo a liquid-to-gel transition, which stabilizes the encapsulated transcripts while repressing their translation. During neuron development, disrupting STAU2 condensation impairs RNP formation and compromises anterograde mRNA delivery to distal dendrites. Conversely, STAU2 overexpression promotes excessive coacervation, resulting in oversized RNP granules with reduced mobility, ultimately hindering dendritic elongation and promoting excessive branching. We further demonstrate that synaptic activity bidirectionally remodels STAU2 condensates in parallel with changes in local translation of bound mRNAs. Notably, aberrant STAU2 condensates emerge as a potential pathological feature in aggregation-prone neurodegenerative disorders. Collectively, our findings establish that STAU2 condensate safeguards the development of postmitotic neurons by orchestrating the dendritic transport and activity-dependent translation of its target mRNAs.