The Role of the Integrated Stress Response (ISR) in Neuropsychiatric Disorders

Abstract The integrated stress response (ISR), a key mechanism of cellular response to various stress signals, is highly conserved across eukaryotes from yeast to humans. A central element of ISR is the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α). This process is regulated by several kinases (PERK, GCN2, HRI and PKR) activated by different contextual cellular stressors. The ISR system plays a critical role in maintaining cell homeostasis and survival under stress. However, its chronic activation can lead to cell dysfunction and programmed cell death. Recent studies indicate that ISR is actively involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, and traumatic brain injury. At the same time, the contribution of ISR to common mental pathologies, including depression, schizophrenia, bipolar disorder, post-traumatic stress disorder and addiction, remains poorly understood. Here, we address current data on the role of IRS in the pathogenesis of these disorders, and discuss the possibilities of pharmacological modulation of ISR pathways in the pathological contexts.