From injury to disease to aging, neurons, like all cells, may face various insults that can impact their function and survival. Although the consequences are substantially dictated by the type, context, and severity of insult, distressed neurons are far from passive. Activation of cellular stress responses aids in the preservation or restoration of nervous system function. However, stress responses themselves can further advance neuropathology and contribute significantly to neuronal dysfunction and neurodegeneration. Here we explore the recent advances in defining the cellular stress responses within neurodegenerative diseases and neuronal injury, and we emphasize axonal injury as a well-characterized model of neuronal insult. We highlight key findings and unanswered questions about neuronal stress response pathways, from the initial detection of cellular insults through the underlying mechanisms of the responses to their ultimate impact on the fates of distressed neurons.


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