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

The integrated stress response (ISR), a key mechanism of cellularresponse to various stress signals, is highly conserved across eukaryotesfrom yeast to humans. A central element of ISR is the phosphorylationof eukaryotic initiation factor 2 alpha (eIF2α). This process isregulated by several kinases (PERK, GCN2, HRI and PKR) activatedby different contextual cellular stressors. The ISR system playsa critical role in maintaining cell homeostasis and survival understress. However, its chronic activation can lead to cell dysfunctionand programmed cell death. Recent studies indicate that ISR is activelyinvolved in the pathogenesis of neurodegenerative diseases, suchas Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis,and traumatic brain injury. At the same time, the contribution ofISR to common mental pathologies, including depression, schizophrenia,bipolar disorder, post-traumatic stress disorder and addiction,remains poorly understood. Here, we address current data on therole of IRS in the pathogenesis of these disorders, and discussthe possibilities of pharmacological modulation of ISR pathwaysin the pathological contexts.