Biology subjects

Balamoti, E.

Publications and source records attributed to Balamoti, E..

2 recordsLinked to original sources

bioRxiv2026

Tau-induced ribosomal collisions impair memory through the activation of the integrated stress response

The formation of new long-term memories is reliant upon the spatial and temporal regulation of mRNA translation. Translational control has been demonstrated to be disrupted in neurodegenerative diseases, which exhibit impairments in both homeostatic translation and memory formation, such as Alzheimers disease (AD) and frontotemporal dementia (FTD). However, the precise mechanisms by which this dysregulation occurs, as well as the pathogenic consequences of this dysregulation have yet to be described. Here we establish that FTD-associated tau mutations impair protein synthesis prior to the onset of memory impairments by slowing ribosomal elongation speed, causing ribosomes to collide upon mRNAs. We reveal that this tau-induced ribosomal collision ultimately impairs memory-associated translation through activation of the integrated stress response (ISR) via GCN2. Pharmacological prevention of this ISR activation not only rescues memory formation in the PS19 mouse model of FTD, but also attenuates neuronal death, decreases tau phosphorylation and accumulation, and improves survival. Collectively, our data elucidates a novel mechanism by which mRNA translation is impaired early in neurodegeneration, identifies several pathological phenotypes which are traceable to impairments in mRNA translation, and highlights the therapeutic potential of rescuing these translational impairments.

neuroscience↗

bioRxiv2025

Mapping the spatiotemporal dynamics of de novo protein synthesis during long-term memory formation

The formation of new associative long-term memory (LTM) following Pavlovian conditioning is dependent upon multiple, temporally distinct windows of mRNA translation. Current methods lack the temporal specificity to robustly characterize the dynamics of protein synthesis throughout the rodent brain following conditioning. Here we resolve these technological limitations and demonstrate that in awake mice, the retro-orbital (RO) injection of azidohomoalanine (AHA) enables the labelling and subsequent visualization of the brain de novo proteome, with labelling periods as short as 30 minutes. Combining this advancement in de novo proteomic labelling with tissue clearing, we identified brain region, cell-type, and neuronal sub-population specific changes in de novo protein synthesis in mice following an auditory threat conditioning paradigm. This approach also allowed us to track the changes in de novo protein synthesis over time, revealing that conditioning-induced changes in mRNA translation exhibit remarkable temporal specificity in brain regions such as the somatosensory cortex. Taken together, our findings highlight how this novel labelling technique can be used to map the highly intricate temporal and spatial dynamics of mRNA translation after behavioral conditioning.

neuroscience↗