Proteostasis

Normal cell function and survival depend on carefully regulated synthesis, folding, trafficking, and degradation of proteins. The balance among these processes is referred to as proteostasis. Proteins undergo maturation and folding in the endoplasmic reticulum. This process is error-prone and can be affected by mutations, errors during transcription or translation, and cellular stressors. Several interacting mechanisms, including the endoplasmic reticulum stress response, the unfolded protein response, and degradation by the ubiquitin-proteasome and the autophagosome-lysosome systems prevent the accumulation of misfolded proteins. Protein misfolding and incorporation into fibrillary structures is a fundamental mechanism of many neurodegenerative disorders. Degeneration results from toxic gain-of-function of the intermediate fibril monomers, promoting the formation of aggregates and initiating a cascade of protein–protein interactions leading to neuronal dysfunction and death, associated with neuroinflammation. These protein aggregates may serve as templates or seeds to elicit aggregation of their respective normal endogenous partners in neighboring cells, leading to disease propagation.