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Review
. 2016 Nov 3;11(1):58.
doi: 10.1186/s13062-016-0161-2.

The struggle by Caenorhabditis elegans to maintain proteostasis during aging and disease

Elise A Kikis  1
Affiliations
Review

The struggle by Caenorhabditis elegans to maintain proteostasis during aging and disease

Elise A Kikis. Biol Direct. .

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.

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Figures

Fig. 1
Fig. 1
Using C. elegans models of protein folding to study the regulation of proteostasis. This review discusses how two different types of folding sensors, disease-associated aggregation-prone proteins and metastable endogenous proteins (shown in blue), have been used to uncover the proteostasis network, reveal how natural variation and genetic background modulate the protein folding environment, reveal how proteostasis declines during aging, and identify small molecule regulators of proteostasis (shown in red). Black lines connect the two categories of folding sensors to the research areas in which each was employed as a tool
Fig. 2
Fig. 2
Disease-Associated Proteins Expressed in C. elegans. a Schematic representation of C. elegans showing body wall muscle cells (red), neuronal cells (blue), and intestinal cells (green). Disease associated proteins are indicated and the arrows point to the tissues in which they have been expressed. b Each box represents a tissue including body wall muscle cells (red), neuronal cells (blue), and intestinal cells (green). The disease-associated proteins that have been expressed in each tissue are indicated in the corresponding box
Fig. 3
Fig. 3
The Proteostasis Network. The pathway for protein synthesis and maturation is shown with specific cellular processes indicated with blue arrows and pathway intermediates indicated in circles. The functional categories of proteins that have been identified as members of the proteostasis network are shown in boxes, with → representing positive regulation and —| representing negative regulation. The thick arrow for on-pathway folding represents the fact that for most proteins under normal non-stress conditions, on-pathway folding predominates over off-pathway folding
Fig. 4
Fig. 4
Genetic Background Affects the Protein Folding Environment. a Age of Huntington’s Disease onset as a function of polyQ repeat length (adapted from Wexler, et. al., (2004) Proc. Natl., Acad. Sci.). b Schematic representation of the decline in proteostasis buffering capacity as the misfolded protein load increases. Three sources of misfolded protein are considered, including destabilizing polymorphisms in the genetic background (red), disease-associate proteins (brown), and sporadic mutation to DNA or accumulated damage during aging (blue). Symptoms associated with neurodegenerative disease or aging are more likely to be observed when the misfolded protein load is sufficiently high (shaded in pink) as compared to normal (green) or intermediate levels (yellow) of misfolding
Fig. 5
Fig. 5
Neuronal Regulation of Protein Misfolding and the Heat Shock Response. a Top: Sensory neurons induce the organismal HSR under conditions of acute thermal stress and block the upregulation of Hsps in non-neuronal tissues under conditions of chronic misfolding but normal temperature. Bottom: Genetic ablation of sensory neurons results in an inability to launch an organismal HSR, but de-repression of Hsp expression results in their upregulation in non-neuronal tissues and concomitant suppression of the aggregation of disease-associated proteins. b Cholinergic signaling at the neuromuscular junction (NMJ). Red dots represent acetylcholine and the acetylcholine receptor (AchR) is indicated. Left: normal conditions; middle: conditions of moderate increase in acetylcholine signaling to upregulation of the AchR; right: extreme increase in acetylcholine signaling due to lack of the inhibitory neurotransmitter GABA. Downstream effects on aggregation and toxicity of disease-associated proteins are indicated. c Schematic graphical representation of the effects of cholinergic signaling on the aggregation of disease associated proteins. The green block represents the narrow window during which acetylcholine signaling is neither too high nor too low to suppress aggregation via the induction of a heat shock response in muscle cells
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