Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging Protein homeostasis, or proteostasis, is essential for maintaining the long-term health of cells. It involves a complex network of molecular interactions that balance protein biosynthesis, folding, translocation, assembly/disassembly, and clearance. Imbalances in this system can lead to the accumulation of misfolded proteins, which can cause severe cellular damage. The cell must adapt to these stresses by sensing damaged proteins and coordinating protective stress response pathways and chaperone networks. Despite the abundance of chaperones and other components of proteostasis, cells appear poorly adapted to chronic proteotoxic stress, particularly in conditions like cancer, metabolic disease, and neurodegenerative disease. This is linked to genes that control aging, connecting stress and protein homeostasis to the health and lifespan of organisms. Chaperones, such as heat shock proteins (Hsps), play a crucial role in regulating protein conformation, protecting nascent polypeptides from misfolding, and facilitating the assembly and disassembly of macromolecular complexes. They are essential for protein folding, and their regulation is influenced by stress-inducible responses. The heat-shock response is mediated by heat-shock transcription factors (HSFs), which are activated in response to various stress signals. This response involves the activation of HSF1, leading to the expression of heat shock genes that help restore protein homeostasis. The heat-shock response is a universal molecular response to various stress stimuli, but there are exceptions, particularly in the brain and during aging. The regulation of the heat-shock response and HSF1 activity by small molecules has provided valuable tools to understand the mechanisms of HSF1 regulation. These include proteasome inhibitors, Hsp90 inhibitors, and other compounds that can activate or suppress the heat-shock response. Protein misfolding and aggregation are common molecular events in many human diseases, including neurodegenerative diseases. These diseases are characterized by the accumulation of misfolded proteins, which can lead to cellular dysfunction and disease. The study of nonmammalian model systems, such as yeast, C. elegans, and Drosophila, has provided insights into the mechanisms of protein conformational diseases and the role of chaperone networks in maintaining protein homeostasis. Aging is a potent modifier of protein homeostasis, and the association with aging is a characteristic aspect of protein conformational diseases. The insulin-like signaling (ILS) pathway, which regulates aging and lifespan, has been shown to modulate aggregation toxicity. The ILS pathway and HSF1 function via stress responses and chaperone networks, and their modulation can influence the aging process and protein aggregation. The challenge to the cell and organism in the face of chronic proteotoxic stress is the global decline in cellular function with deleterious consequences on viability. TheProteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging Protein homeostasis, or proteostasis, is essential for maintaining the long-term health of cells. It involves a complex network of molecular interactions that balance protein biosynthesis, folding, translocation, assembly/disassembly, and clearance. Imbalances in this system can lead to the accumulation of misfolded proteins, which can cause severe cellular damage. The cell must adapt to these stresses by sensing damaged proteins and coordinating protective stress response pathways and chaperone networks. Despite the abundance of chaperones and other components of proteostasis, cells appear poorly adapted to chronic proteotoxic stress, particularly in conditions like cancer, metabolic disease, and neurodegenerative disease. This is linked to genes that control aging, connecting stress and protein homeostasis to the health and lifespan of organisms. Chaperones, such as heat shock proteins (Hsps), play a crucial role in regulating protein conformation, protecting nascent polypeptides from misfolding, and facilitating the assembly and disassembly of macromolecular complexes. They are essential for protein folding, and their regulation is influenced by stress-inducible responses. The heat-shock response is mediated by heat-shock transcription factors (HSFs), which are activated in response to various stress signals. This response involves the activation of HSF1, leading to the expression of heat shock genes that help restore protein homeostasis. The heat-shock response is a universal molecular response to various stress stimuli, but there are exceptions, particularly in the brain and during aging. The regulation of the heat-shock response and HSF1 activity by small molecules has provided valuable tools to understand the mechanisms of HSF1 regulation. These include proteasome inhibitors, Hsp90 inhibitors, and other compounds that can activate or suppress the heat-shock response. Protein misfolding and aggregation are common molecular events in many human diseases, including neurodegenerative diseases. These diseases are characterized by the accumulation of misfolded proteins, which can lead to cellular dysfunction and disease. The study of nonmammalian model systems, such as yeast, C. elegans, and Drosophila, has provided insights into the mechanisms of protein conformational diseases and the role of chaperone networks in maintaining protein homeostasis. Aging is a potent modifier of protein homeostasis, and the association with aging is a characteristic aspect of protein conformational diseases. The insulin-like signaling (ILS) pathway, which regulates aging and lifespan, has been shown to modulate aggregation toxicity. The ILS pathway and HSF1 function via stress responses and chaperone networks, and their modulation can influence the aging process and protein aggregation. The challenge to the cell and organism in the face of chronic proteotoxic stress is the global decline in cellular function with deleterious consequences on viability. The