The intrinsic and extrinsic factors that contribute to proteostasis decline and pathological protein misfolding.

Proteostasis refers to the ability of cells to maintain the health of the proteome. Highly conserved quality control mechanisms exist to maintain proteostasis. These include the heat shock response, the unfolded protein response, and protein clearance/degradation pathways. Together, these mechanisms and others comprise the proteostasis network. This network is under constant assault and is strikingly sensitive to changes in the protein folding environment, resulting in proteostasis collapse under certain conditions. Here, the intrinsic and extrinsic stresses experienced by the proteostasis network are explored. The intrinsic stresses include genetic background as well as transcriptional and translational fidelity. These cause changes in the abundance or amino acid sequence of cellular proteins. Extrinsic stresses refer to environmental perturbation of the proteome, such as those caused by temperature stress, oxidative stress, air pollution and cigarette smoke. As the stress to the proteome exceeds the capacity of the proteostasis network, progressive neurodegenerative diseases of aging, such as Alzheimer's disease and Huntington's disease are more likely to ensue.