PKR Shapes Integrated Stress Response Dynamics to Coordinate Structural and Functional Recovery After Peripheral Nerve Injury

Peripheral nerve regeneration requires precise regulation of axonal proteostasis and myelination to restore sensorimotor function after injury. However, whether stress-responsive translational control pathways contribute to this process in vivo remains largely unknown. Here, we show that the integrated stress response (ISR), a conserved signaling pathway that fine-tunes the neuronal proteome through kinases that sense intracellular stress, is dynamically activated after sciatic nerve injury and that the RNA-dependent ISR kinase, PKR, shapes the temporal organization of this response during nerve degeneration and regeneration. Peripheral nerve injury triggers a spatially and temporally organized pattern of ISR activation along the injured sciatic nerve. PKR deficiency delays motor recovery after nerve crush without affecting axonal density restoration, while altering ISR activation dynamics and the abundance of nerve integrity markers during degeneration and regeneration. Moreover, loss of PKR impairs the ultrastructural recovery of regenerated nerves, resulting in reduced myelinated axon density and altered g-ratios. Together, these findings identify PKR as a key regulator that couples ISR dynamics to ultrastructural remodeling and functional recovery after peripheral nerve injury.