Figure 1. Intra- and extracellular stressors drive NDs.

Pathological alterations in normal homeostatic mechanisms of protein genesis, trafficking, and degradation cause the accumulation of misfolded proteins. During the action of normal homeostatic mechanisms, polypeptides are translated outside the nucleus from mRNA transcribed from nuclear DNA and are then folded normally and trafficked to specific locations within the cells. Old proteins are marked for degradation and are trafficked to the lysosome for degradation. In cases of DNA mutations, the translated polypeptides have a higher probability of folding incorrectly, thereby generating degradation-resistant proteins that accumulate to drive pathologies. In addition, intracellular stressors, such as an abundance of ROS generated within cellular mitochondria, or extracellular stressors, such as infections or aberrant proinflammatory cytokine responses to these infections from immune cells, may cause aberrant biogenesis or misfolding of proteins, thus leading to their accumulation. Illustration adapted with permission from Noelle Burgess at the Institute for Cellular Engineering of Johns Hopkins University.