Lai, K.-O. | Search bioRxiv

bioRxiv2026

Heterogeneous and specific localization of mRNAs at dendritic spine and its dependence on microtubule entry and kinesin motor

Local mRNA translation near neuronal synapses is crucial for structural plasticity during brain development and memory formation. Whereas mRNAs are transported from soma to dendrites as individual ribonucleoprotein (RNP) granules, how do they subsequently localize at synapses is unclear. In particular, whether different dendritic mRNAs might display differential synaptic localization and interact with specific postsynaptic proteins remains unexplored. Here we found that two well-known dendritic mRNAs, Actb and Camk2a, are targeted to different subdomains of dendritic spines and delivered to different spine populations after synaptic stimulation. Surprisingly, the induced mRNA localization to dendritic spines is associated with microtubule (MT) entry and specifically requires the MT-associated motor KIF5A. Proximity-labelling proteomics further identifies distinct postsynaptic proteins enriched by Actb and Camk2a, from which we uncover the cytoskeletal protein Septin7 to be co-localized with the two mRNAs at different subdomains of dendritic spines. Our study reveals an unexpectedly specific mRNA localization mechanism at synapses and demonstrates proximity-labelling as a useful approach to map their synaptic partners.

neuroscience↗

bioRxiv2026

NORAD orchestrates KLC1-mediated SFPQ transport via liquid-liquid phase separation

Neuronal function requires precise long-distance axonal transport mediated by molecular motors and RNA-binding proteins like SFPQ, though regulatory mechanisms remain poorly defined. We identify long non-coding RNA NORAD as a master regulator of this process through liquid-liquid phase separation (LLPS). While SFPQ and kinesin-1 mediate cargo delivery, the specific RNA coordinating their interaction was unknown. We demonstrate NORAD directly binds kinesin light chain 1 (KLC1) and promotes SFPQ condensation into dynamic LLPS droplets, enabling efficient transport. CRISPR-assisted mapping and functional assays show NORAD depletion disrupts granule dynamics, impairs neuroprotective mRNA localization, and induces axonal degeneration. In vitro reconstitution confirms NORAD-KLC1 synergy enhances SFPQ phase separation, and neuron-specific knockout mice exhibit motor deficits with reduced neuronal density. These findings establish the first evidence of lncRNA NORAD-mediated LLPS in axonal transport, revealing a new paradigm for RNA-guided neuronal maintenance.

molecular biology↗