Abstract
The presence of only small amounts of misfolded protein is an indication of a healthy proteome. Maintaining proteome health, or more specifically, "proteostasis," is the purview of the "proteostasis network." This network must respond to constant fluctuations in the amount of destabilized proteins caused by errors in protein synthesis and exposure to acute proteotoxic conditions. Aging is associated with a gradual increase in damaged and misfolded protein, which places additional stress on the machinery of the proteostasis network. In fact, despite the ability of the proteostasis machinery to readjust its stoichiometry in an attempt to maintain homeostasis, the capacity of cells to buffer against misfolding is strikingly limited. Therefore, subtle changes in the folding environment that occur during aging can significantly impact the health of the proteome. This decline and eventual collapse in proteostasis is most pronounced in individuals with neurodegenerative disorders such as Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease that are caused by the misfolding, aggregation, and toxicity of certain proteins. This review discusses how C. elegans models of protein misfolding have contributed to our current understanding of the proteostasis network, its buffering capacity, and its regulation. REVIEWERS: This article was reviewed by Luigi Bubacco, Patrick Lewis and Xavier Roucou.