Figure 2.

a–b. Proteostasis networks buffer metastable and misfolded species, ensuring normal cellular function. c–d. Failure of proteostasis networks to buffer misfolding results in onset of dysfunction. Accumulated protein damage, proteotoxic stresses and aging all contribute to the increase in misfolding and thus to the decline in the proteostasis network capacity. Either a single dominant mutation (d), or a cumulative effect of milder destabilizing mutations and polymorphisms (c) may lead to the cell-specific dysfunction of sensitized pathways and protein complexes, by competing for a shared limiting component(s) of the proteostasis network.