Research Findings

2026.07.24

Activity-dependent ribosome profiling reveals the landscape of canonical and non-canonical translation in brain tissue

Nat Commun. 17, 6179 (2026). https://doi.org/10.1038/s41467-026-74968-z

Suryawanshi N1,2,6, Uchida H3,4,6, Endo R1, Sato K1, Satoh D3, Tsumagari K5, Imami K5, Mikuni T3, Tanaka M1,2

  1. Laboratory for Protein Conformation Diseases, RIKEN Center for Brain Science.
  2. Department of Biomedical Sciences and Engineering, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo.
  3. Department of Cellular Neuropathology, Brain Research Institute, Niigata University.
  4. Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University.
  5. Proteome Homeostasis Research Unit, RIKEN Center for Integrative Medical Sciences.
  6. These authors contributed equally.

Abstract

Neural activity-dependent translation is essential for synaptic plasticity and diverse brain functions. Translation involves not only canonical main open reading frames (mORFs) but also upstream ORFs (uORFs), which may regulate mORF expression. However, due to technical limitations, systematic investigation of activity-dependent uORFs and mORFs in brain tissues remains challenging. Here, we developed a ribosome tagging and purification strategy that bypasses the prolonged turnover of ribosomal proteins, enabling ribosome profiling with one-hour temporal resolution after neural stimulation. Applying this strategy to mouse hippocampal slices undergoing long-term potentiation, we identify hundreds of activity-induced mORFs and uORFs, including a previously unknown uORF from Egr1. We demonstrate that this Egr1-uORF translation is tightly regulated by neuronal activity, and its encoded peptide interacts with peroxisomal machinery, suggesting a potential link between synaptic stimulus and peroxisome biology. This study provides a useful technique and resources for deciphering molecular mechanisms underlying activity- and translation-dependent brain functions in health and disease.

*Reprinted under the terms of the Creative Commons Attribution 4.0 International License.

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