The integrated stress response in neurodegenerative diseases

The integrated stress response (ISR) is a conserved network in eukaryotic cells that mediates adaptive responses to diverse stressors. The ISR pathway ensures cell survival and homeostasis by regulating protein synthesis in response to internal or external stresses. In recent years, the ISR has emerged as an important regulator of the central nervous system (CNS) development, homeostasis and pathology. Dysregulation of ISR signaling has been linked to several neurodegenerative diseases. Intriguingly, while acute ISR provide neuroprotection through the activation of cell survival mechanisms, prolonged ISR can promote neurodegeneration through protein misfolding, oxidative stress, and mitochondrial dysfunction. Understanding the molecular mechanisms and dynamics of the ISR in neurodegenerative diseases aids in the development of effective therapies. Here, we will provide a timely review on the cellular and molecular mechanisms of the ISR in neurodegenerative diseases. We will highlight the current knowledge on the dual role that ISR plays as a protective or disease worsening pathway and will discuss recent advances on the therapeutic approaches that have been developed to target ISR activity in neurodegenerative diseases.