The integrated stress response in the brain: cell type-specific functions in health and neurological disorders

The integrated stress response (ISR) is an evolutionarily conserved signaling network that regulates protein synthesis in response to diverse cellular stressors to promote stress adaptation. The ISR also responds to physiological stimuli to modify the cellular proteome in an activity-dependent manner. Many common brain pathologies, including neurodegenerative and neurodevelopmental disorders, induce chronic cellular stress and subsequent ISR activation, which substantially contributes to disease progression. Importantly, various brain cell types exhibit disparate levels of sensitivity to cellular stress and differ in how the activation of the ISR influences their physiology. In this review, we highlight cell type-specific roles of the ISR in brain health and disease. We also discuss how therapeutically targeting the ISR in pathological states should account for the cell types being affected.