ABSTRACT
A healthy proteome has little to no misfolded protein. A network of cellular factors that together comprises the “proteostasis network” contributes to the health of proteome by maintaining what is known as proteostasis. Transient fluctuations in the overall load of misfolded protein occur due to errors caused by the protein synthesis machinery as well as by exposure to environmental conditions that may be damaging to proteins. The proteostasis network includes molecular chaperones and protein degradation machinery that must respond to these fluctuations by readjusting their stoichiometry and thereby creating a buffer against misfolding. Nonetheless, the buffering capacity of the proteostasis network is much more limited than one might expect. Even subtle changes to the load of misfolded protein can lead to a precipitous decline in proteostasis. This decline occurs during aging when the proteome has been compromised by several years’ worth of accumulated damage, and is especially pronounced in individuals with progressive neurodegenerative disorders that are caused by the misfolding of certain proteins. This chapter covers use of Caenorhabditis elegans as a genetic model system to study the regulation of proteostasis during aging and the ways in which that affects the misfolding of neurodegenerative disease-associated proteins.
