HSF1-Controlled and Age-Associated Chaperone Capacity in Neurons and Muscle Cells of C. elegans

Abstract

Protein stability under changing conditions is of vital importance for the cell and under the control of a fine-tuned network of molecular chaperones. Aging and age-related neurodegenerative diseases are directly associated with enhanced protein instability. Employing C. elegans expressing GFP-tagged luciferase as a reporter for evaluation of protein stability we show that the chaperoning strategy of body wall muscle cells and neurons is significantly different and that both are differently affected by aging. Muscle cells of young worms are largely resistant to heat stress, which is directly mediated by the stress response controlled through Heat Shock Transcription Factor 1. During recovery following heat stress the ability to refold misfolded proteins is missing. Young neurons are highly susceptible to chronic heat stress, but show a high potency to refold or disaggregate proteins during subsequent recovery. The particular proteome instability in neurons results from a delayed induction of the heat shock response. In aged neurons protein stability is increased during heat stress, whereas muscle cells show enhanced protein instability due to a deteriorated heat shock response. An efficient refolding activity is absent in both aged tissues. These results provide molecular insights into the differential protein stabilization capacity in different tissues and during aging.

Firefly luciferase mutants as sensors of proteome stress

“…This suggests that the proteostasis machinery in neuronal cells is better equipped to dispose of aggregated proteins. This observation is in agreement with a previous report which states that the chaperoning capacity of body-wall muscle cells is different from that of neuronal cells (Kern et al, 2010). Interestingly, we also observed differences between the muscle and the neuronal cells in their ability to maintain protein homeostasis during aging (Figure 35).…”

“…One possible explanation are differences in the ability of tissues to mount a HSF1 mediated adaptive stress response. It has been shown previously that neuronal cells are less efficient in mounting a stress response when compared with muscle cells and consequently they are more sensitive to stress (Kern et al, 2010). The molecular basis for this observation is still unclear.…”

Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis

“…For example, thermal stress activates the heat shock transcription factor (Hsf) to up-regulate heat shock proteins (HSPs), including protein folding chaperones, which counteract protein unfolding at elevated temperatures. In contrast, thermal stress fails to robustly activate Hsf in aged worms and mammalian cells (Heydari et al, 2000;Kern et al, 2010b). Together with numerous findings that genetic enhancement of Hsf function enables lifespan extension (Baird et al, 2014;Hsu et al, 2003), these observations hint at the existence of a direct mechanistic link between longevity and protein folding homeostasis.…”

“…Many aging studies have found that Hsf activation by thermal stress is compromised in old cells. For example, Hsf activity in worms decreases with age in a tissue specific manner: muscle cells are unresponsive to heat stress, while neurons maintain normal Hsf inducibility (Kern et al, 2010a). Additional worm studies have found that certain genetic mutations extend lifespan in an Hsf-dependent manner (Hsu et al, 2003).…”

Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery

“…Neurons and muscle cells have different functions and metabolic requirements so it might not be surprising that they respond differently to manipulations promoting overall lifespan extensions in the context of proteotoxicity. Indeed, neurons and muscle cells appear to have different capabilities in responding to protein misfolding during aging (Kern et al, 2010). Thus, the predictive value of muscle-based models for neurodegenerative disorders needs to be interpreted with caution.…”