Talks

The ALS research community has embraced stress granule dynamics as a potential central pathway in ALS pathogenesis. In the face of adverse growth conditions, stress granules serve to shift translation towards the production of pro-survival factors. Many teams have focused on how these structures might serve as precursors for the TDP-43 inclusions observed in patient neurons and thus stress granule formation is viewed has neurotoxic. Consequently, many teams have charted a course to identify ways to inhibit stress granule formation as a potential therapeutic strategy.
A counterview to the role of stress granules in ALS/FTD is that they are neuroprotective and that the inability to launch a robust stress granule response lies at the heart of neuronal vulnerability in ALS/FTD. In support of this, we have previously reported that TDP-43 translocation to the cytoplasm and consequent nuclear depletion is linked to a decrease in the expression of the core stress granule assembly factor G3BP1. We subsequently confirmed this result at the mRNA level in human ALS-FTD cortex. Taken together, we have hypothesized that a deficiency in G3BP1 expression could compromise neuronal ability to withstand assault by stressors (both internal and external) and thus render neurons more vulnerable. We have tested this hypothesis in vivo and have now further defined the mechanism by which TDP-43 regulates G3BP1 and propose this as a unique therapeutic opportunity.

Long non-coding RNAs (lncRNA) is emerging as a key regulatory RNA in the brain. The activity of lncRNAs in neurons have been majorly limited to the nucleus and our understanding of their functions in subcellular space remains elusive. We have used the genome-wide transcriptomic profiling of total RNA isolated from the synaptic compartment and identified synapse-enriched lncRNAs from the mouse hippocampus. Among these transcripts, we find a synapse-centric role for a novel lncRNA, SynLAMP (Synapse-enriched LncRNA Associated with Memory and Plasticity). SynLAMP is specifically transported to the synaptic compartment upon contextual fear conditioning (CFC). We observed that CFC triggers interaction between SynLAMP and translation repressor FUS. The knockdown of SynLAMP prevents activity-induced dendritic translation. Our data suggests that SynLAMP functions as an activity-regulated molecular decoy to sequester translation repressor FUS. We find that the knockdown of SynLAMP partially occludes the fear memory. The decoy function of synaptic lncRNAs was further favoured by our findings on Cerox1 (Cytoplasmic endogenous regulator of oxidative phosphorylation 1), a synapse-enriched lncRNA that acts as a competitive decoy for miRNAs. We observed that Cerox1 levels decrease following sleep loss, a condition known to impair memory. Sleep deprivation or Cerox1 knockdown led to reduced mitochondrial Electron Transport Chain (ETC) activity and diminished ATP production, whereas overexpression of Cerox1 was sufficient to restore ETC function and ATP levels, even under conditions of sleep deprivation. This regulation is mediated by Cerox1’s ability to sequester miRNAs that target both Cerox1 and essential subunits of ETC complex I, thereby sustaining their expression in a sleep-dependent manner. Importantly, overexpression of Cerox1 alleviated memory deficits caused by sleep loss, while a Cerox1 variant lacking miRNA-binding sites failed to produce such effects. Collectively, these findings uncover a previously unrecognized mechanism of memory regulation mediated by the decoy activity of synapse-enriched lncRNAs.

Long non-coding RNAs (lncRNA) is emerging as a key regulatory RNA in the brain. The activity of lncRNAs in neurons have been majorly limited to the nucleus and our understanding of their functions in subcellular space remains elusive. We have used the genome-wide transcriptomic profiling of total RNA isolated from the synaptic compartment and identified synapse-enriched lncRNAs from the mouse hippocampus. Among these transcripts, we find a synapse-centric role for a novel lncRNA, SynLAMP (Synapse-enriched LncRNA Associated with Memory and Plasticity). SynLAMP is specifically transported to the synaptic compartment upon contextual fear conditioning (CFC). We observed that CFC triggers interaction between SynLAMP and translation repressor FUS. The knockdown of SynLAMP prevents activity-induced dendritic translation. Our data suggests that SynLAMP functions as an activity-regulated molecular decoy to sequester translation repressor FUS. We find that the knockdown of SynLAMP partially occludes the fear memory. The decoy function of synaptic lncRNAs was further favoured by our findings on Cerox1 (Cytoplasmic endogenous regulator of oxidative phosphorylation 1), a synapse-enriched lncRNA that acts as a competitive decoy for miRNAs. We observed that Cerox1 levels decrease following sleep loss, a condition known to impair memory. Sleep deprivation or Cerox1 knockdown led to reduced mitochondrial Electron Transport Chain (ETC) activity and diminished ATP production, whereas overexpression of Cerox1 was sufficient to restore ETC function and ATP levels, even under conditions of sleep deprivation. This regulation is mediated by Cerox1’s ability to sequester miRNAs that target both Cerox1 and essential subunits of ETC complex I, thereby sustaining their expression in a sleep-dependent manner. Importantly, overexpression of Cerox1 alleviated memory deficits caused by sleep loss, while a Cerox1 variant lacking miRNA-binding sites failed to produce such effects. Collectively, these findings uncover a previously unrecognized mechanism of memory regulation mediated by the decoy activity of synapse-enriched lncRNAs.

Following the discovery that the RNA-binding proteome is far larger than previously anticipated (Castello et al., 2012), riboregulation, the direct control of protein function by RNA, has begun to emerge as a new paradigm of biological control (Horos et al., 2019; Huppertz et al., 2022; Chatterjee et al., 2024; Hentze et al., 2025). We are beginning to understand molecular mechanisms of riboregulation, and I will discuss their implications for cell biology, metabolism and disease mechanisms as well as the new therapeutic opportunities. I will also share very recent unpublished data that add a new dimension to the concept of riboregulation…

Castello, A., B. Fischer, K. Schuschke, R. Horos, B.M. Beckmann, C. Strein, N.E. Davey, D.T. Humphreys, T. Preiss, L.M. Steinmetz, J. Krijgsveld and M.W. Hentze. Insights into RNA biology from an atlas of mammalian mRNA-
binding proteins. Cell 149, 1393-1406, 2012.

Hentze, M.W., P. Sommerkamp, V. Ravi and F. Gebauer, Rethinking RNA-binding proteins: riboregulation challenges prevailing views. Cell, in press, 2025.

Horos, R., M. Büscher, R. Kleinendorst, A.-M. Alleaume, A.K. Tarafder, T. Schwarzl, D. Dziuba, C. Tischer, E.M. Zielonka, A. Adak, A. Castello, W. Huber, C. Sachse and M.W. Hentze, The small non-coding vault RNA1-1 acts
as a riboregulator of autophagy. Cell 176, 1054-1067, 2019.

Huppertz, I., J.I. Perez-Perri, P. Mantas, T. Sekaran, T. Schwarzl, F. Russo, D. Ferring-Appel, L. Dimitrova-Paternoga, E. Kafkia, J. Hennig, P.A. Neveu, K. Patil and M.W. Hentze. Riboregulation of Enolase 1 Activity Controls
Glycolysis and Embryonic Stem Cell Differentiation. Mol. Cell 82, 2666-2680, 2022.

Chatterjee, A., M. Noble, T. Sekaran, V. Ravi, D. Ferring-Appel, T. Schwarzl, R. Rampelt and M.W. Hentze. RNA promotes mitochondrial import of F1-ATP synthase subunit alpha (ATP5A1). doi: https://doi.org/10.1101/2024.08.19.608659.

The ongoing evolutionary arms race between bacteria and their predatory phages gives rise to the evolution of different anti-phage defense systems. Among these, CRISPR-Cas represents an RNA-mediated adaptive and heritable immune system that protects the bacteria and archaea against the invasion of mobile genetic elements such as phages and plasmids. Exploitation of this immune system gave rise to a widely acclaimed and versatile genome editing technology referred as CRISPR/Cas9 and several variants thereof. In this talk, I will emphasize the centrality of RNA in orchestrating the defense response. The defense mechanism proceeds via three distinct stages: (i) acquisition of immunological memory from the foreign genetic elements and storing it in the genome, (ii) retrieving this immunological memory in the form of RNA and (iii) using this RNA as a guide for target recognition and cleavage. This talk will introduce CRISPR-Cas as a prokaryote-specific defense response and highlight the molecular mechanism that underlie the fascinating functional diversity. Finally, I will provide a compelling narrative how mechanistic understanding of this defense system was instrumental for repurposing them as precision genetic scissors.