July 13th, 2025
Recent Publications Harnessing the Power of Translatomics
Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.
In this week’s Sunday papers,
- Rhine et al. find that neuronal aging leads to mislocalization of RNA-binding proteins, dysfunctional stress granules, and impaired translation.
- Mestre-Fos et al. show that eIF3 binds to the 3′ UTRs of polyadenylated mRNAs in neural progenitor cells, promoting translation by facilitating mRNA circularization.
- Seluzicki et al. find that neurons respond to heat shock by transiently slowing translation via eEF2 phosphorylation, enabling rapid recovery without activating a full integrated stress response.
Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress
Nature Neuroscience, 2025
Rhine, K., Li, R., Kopalle, H.M., Rothamel, K., Ge, X., Epstein, E., Mizrahi, O., Madrigal, A.A., Her, H.-L., Gomberg, T.A., Hermann, A., Schwartz, J.L., Daniels, A.J., Manor, U., Ravits, J., Signer, R.A.J., Bennett, E.J. and Yeo, G.W.
This study examines how neuronal aging disrupts RNA regulation and contributes to neurodegenerative disease vulnerability. The authors used direct reprogramming to convert aged human fibroblasts into induced neurons (iNs), preserving age-related molecular signatures. Aged neurons showed widespread depletion and cytoplasmic mislocalization of RNA-binding proteins (RBPs), including core splicing factors like TDP-43, which is linked to amyotrophic lateral sclerosis and frontotemporal dementia. In contrast to young neurons, where splicing proteins are mostly nuclear, aged neurons exhibited disrupted RNA processing and altered splicing patterns.
Importantly, the study shows that aged neurons are under chronic cellular stress, which impairs normal stress granule dynamics. Instead of transient and functional assemblies, stress granules in aged neurons were persistent, gel-like, and failed to incorporate key RBPs such as TDP-43. These dysfunctional granules were linked to compromised protein quality control systems, including reduced ubiquitination and chaperone activity (e.g., HSP90α), resulting in reduced resilience to acute stress.
To assess whether these stress granules influenced protein synthesis, the authors performed ribosome profiling (Ribo-seq). While thousands of transcripts showed decreased translation efficiency in aged neurons, G3BP1- and Caprin1-bound transcripts did not, suggesting that chronic stress granules do not directly regulate translation. Additionally, granules formed under stress were smaller and misshapen, indicating impaired dynamics.
Together, these findings suggest that RBP mislocalization and stress granule dysfunction are intrinsic, early features of neuronal aging and may contribute to the development of sporadic neurodegenerative diseases.
Learn more about EIRNABio’s ribosome profiling services here.
eIF3 engages with 3’-UTR termini of highly translated mRNAs
eLife, 2025
Mestre-Fos, S., Ferguson, L., Trinidad, M.I., Ingolia, N.T. & Cate, J.H.D.
This study investigates the role of eukaryotic initiation factor 3 (eIF3) in early differentiation of human pluripotent stem cell‑derived neural progenitor cells (NPCs). Using Quick‑irCLIP and alternative polyadenylation (APA)‑Seq, the authors demonstrate that eIF3 crosslinks predominantly to the 3′‑UTR termini of multiple mRNA isoforms, located adjacent to the poly(A) tail, and this binding depends on polyadenylation.
Ribosome profiling revealed that mRNAs with stronger eIF3 crosslinking at their 3′‑UTR ends also exhibit higher ribosome occupancy, indicating increased translation. Notably, non‑polyadenylated histone mRNAs lack eIF3 binding, reaffirming the poly(A)‑dependence. The results suggest a general mechanism in which eIF3 contributes to mRNA circularization, bringing 5′ and 3′ ends into proximity, possibly facilitating successive rounds of translation. Unlike canonical models of eIF3 binding at 5′‑UTRs, this novel 3′‑end association appears to reflect broad engagement with highly translated transcripts, rather than sequence‑specific regulation.
The authors propose that this structural role of eIF3 helps maintain high translation levels across active mRNAs. This discovery expands our understanding of eIF3’s functions beyond initiation to include the 3′‑UTR in translation control.
Learn more about EIRNABio’s ribosome profiling services here.
Regulation of translation elongation and integrated stress response in heat-shocked neurons
Cell Reports, 2025
Seluzicki, C.M., Razavi-Mohseni, M., Türker, F., Patel, P., Hua, B., Beer, M.A., Goff, L. and Margolis, S.S.
This study reveals that neurons respond to heat shock not by triggering a classic integrated stress response (ISR), but by implementing a refined translational arrest. Polysome profiling showed a dramatic reduction in polysome peaks and an accumulation of monosomes in heat-shocked neurons. Heat‑shocked neurons globally suppress protein synthesis by phosphorylating eukaryotic elongation factor 2 (eEF2), which slows ribosome translocation. Ribosome profiling and RNA‑seq during heat shock show that slowly translating ribosomes are loaded on mRNAs, and are poised to resume translation upon recovery.
Importantly, quick restoration to normal temperature (within ~1 hour) enables rapid dephosphorylation of eEF2 and resumption of translation, crucial for neuronal survival. Once recovery begins, the ISR briefly activates, and neurons become sensitive to the ISR inhibitor ISRIB, which further boosts protein synthesis and enhances survival.
Overall, neurons adopt a hybrid stress response to heat shock: a temporary arrest via elongation slowdown, preserving translational capacity, that enables a swift restart upon cooling, followed by a controlled ISR to fine-tune recovery. This nuanced mechanism highlights neuron-specific strategies to maintain proteostasis under thermal stress.
Learn more about EIRNABio’s ribosome profiling and polysome profiling services here.