How does proteostasis network dysfunction contribute to disease?

The proteostasis network maintains protein homeostasis through coordinated protein synthesis, folding, trafficking, and degradation. Key components include molecular chaperones (Hsp70, Hsp90, chaperonins), the unfolded protein response (UPR in ER, mitochondrial UPR), the ubiquitin-proteasome system (UPS), and autophagy. Network decline with aging or genetic mutations causes protein aggregation diseases: Alzheimer's (amyloid-beta, tau), Parkinson's (alpha-synuclein), Huntington's (polyQ expansions), and ALS (SOD1, TDP-43). Cancer cells co-opt proteostasis for survival under stress. Therapeutic strategies include pharmacological chaperones, proteostasis regulators (HSF1 activators, UPR modulators), proteasome inhibitors (cancer), and autophagy modulators. Systems biology approaches map proteostasis network and identify intervention points.