Fischbach F, Grosshans HK, Binkle-Ladisch L, Friese MA.
Neurons are highly specialized cells whose function depends on dynamic regulation of gene expression. With increasing subcellular compartmentalization, neuronal gene expression becomes less dependent on transcription in the perinuclear region and tends to be increasingly controlled by local translation. The integrated stress response is a central, evolutionarily conserved pathway of translational regulation that maintains neuronal homeostasis through precise control of protein synthesis. Transient cellular stress, such as neuronal infection, adaptively activates this pathway, whereas persistent dysregulation, as observed in neuroinflammation and neurodegeneration, promotes neuronal dysfunction and damage. Here, we summarize key neuron-specific mechanisms governing translational homeostasis and discuss adaptive and detrimental molecular processes associated with neurological disease. Understanding this tightly regulated pathway and its context-dependent effects provides a framework for identifying mechanisms of neuronal vulnerability and for developing therapeutic strategies that target translational control in neurological disorders, while preserving its essential adaptive functions under physiological and acute stress conditions.
Cell Chem Biol. 2026 Sep 14:S2451
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