Integrated Stress Response in Neuronal Pathology and in Health

Neurodegeneration involves progressive pathological loss of a specific population of neurons, glial activation, and dysfunction of myelinating oligodendrocytes leading to cognitive impairment and altered movement, breathing, and senses. Neuronal degeneration is a hallmark of aging, stroke, drug abuse, toxic chemical exposure, viral infection, chronic inflammation, and a variety of neurological diseases. Accumulation of intra- and extracellular protein aggregates is a common characteristic of cell pathologies. Excessive production of reactive oxygen species and nitric oxide, induction of endoplasmic reticulum stress, and accumulation of misfolded protein aggregates have been shown to trigger a defensive mechanism called integrated stress response (ISR). Activation of ISR is important for synaptic plasticity in learning and memory formation. However, sustaining of ISR may lead to the development of neuronal pathologies and altered patterns in behavior and perception.