Direct interaction of ribosomes with postsynaptic proteins gives rise to a privileged local synaptic translatome

Bourke, A. M.; Massari, M.; Tushev, G.; Wu, M.; Desch, K.; Guerreiro Mota, S.; Staab, A.; Ciirdaeva, E.; Langer, J. D.; Liu, F.; Schuman, E. M.

doi:10.64898/2026.02.27.708433

bioRxiv · 10.64898/2026.02.27.708433

Direct interaction of ribosomes with postsynaptic proteins gives rise to a privileged local synaptic translatome

Bourke, A. M.·Massari, M.·Tushev, G.·Wu, M.·Desch, K.·Guerreiro Mota, S.·Staab, A.·Ciirdaeva, E.·Langer, J. D.·Liu, F.·Schuman, E. M.

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Abstract

Ribosomes and thousands of mRNAs are localized near synapses to support local protein synthesis. Little is known, however, about how ribosomes are positioned and maintained in dendritic spines- the primary postsynaptic sites of excitatory neurotransmission. Here, using proximity labeling-mass spectrometry, we mapped the interactome of postsynaptic ribosomes, and discovered an unexpected interaction with AMPA receptor complex proteins. Co-immunoprecipitation and crosslinking mass spectrometry using rat cortical synaptosomes showed a direct, mRNA-independent interaction between postsynaptic proteins and intact ribosomes. Immunoprecipitation-ribosome profiling (IP-Ribo-seq) revealed not only the complete synaptic translatome but also that the AMPA receptor-associated subpopulation of synaptic ribosomes preferentially translates mRNAs encoding proteins related to post-synaptic density (PSD) scaffolding and cytoskeletal dynamics. Translation of one of the mRNA targets, Camk2a, was reduced in spines following ER sequestration of endogenous GluA1. Together, these results reveal a role for PSD proteins in positioning ribosomes near the postsynaptic membrane, providing a mechanism to couple synaptic activity with the local production of proteins needed for structural remodeling.

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Bourke, A. M., Massari, M., Tushev, G., Wu, M., Desch, K., Guerreiro Mota, S., Staab, A., Ciirdaeva, E., Langer, J. D., Liu, F., Schuman, E. M.. 2026-02-27. Direct interaction of ribosomes with postsynaptic proteins gives rise to a privileged local synaptic translatome. https://doi.org/10.64898/2026.02.27.708433

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