Editors' ChoiceChaperones

A Different Response to Acute and Chronic Stress

Sci. Signal.  30 Aug 2011:
Vol. 4, Issue 188, pp. ec238
DOI: 10.1126/scisignal.4188ec238

Cells and organisms have evolved quality control systems for sensing and responding to damaged and misfolded proteins, such as the induction of molecular chaperones through the heat shock transcription factor HSF-1 that occurs during the heat shock response (HSR). However, these systems fail to effectively control protein aggregation—and its deleterious consequences—in various disorders associated with chronic protein misfolding. Noting that the HSR in the nematode Caenorhabditis elegans is under neuronal control, Prahlad and Morimoto investigated the role of neuronal activity in the response to the chronic presence of abnormal proteins. Whereas C. elegans bearing loss-of-function mutations specifically affecting AFD thermosensory neurons and AIY interneurons (gcy-8 and ttx-3, respectively) show a decreased global HSR, these neuronal loss-of-function mutations led to decreased aggregation of a protein misfolding reporter (Q44::YFP, consisting of 44 glutamine residues fused to yellow fluorescent protein) expressed in intestinal cells. These mutations also decreased aggregation of Q35::YFP expressed in muscle cells and of a mutant aggregation-prone form of superoxide dismutase (SOD-1G93A) associated with amyotrophic lateral sclerosis, and attenuated a decrease in motility caused by muscle Q35, developmental defects associated with SOD-1G93A, and toxicity associated with misfolding of an isoform of paramyosin. Similarly, blocking the calcium-dependent neuronal secretion of dense core vesicles by deleting unc-31 decreased aggregation of Q44::YFP in intestinal cells and Q35::YFP in muscle. Knocking down HSF-1 restored protein aggregation in gcy-8 or unc-31 mutant worms, whereas combining gcy-8 with chronic expression of misfolded aggregation-prone proteins (but not either alone) elicited an HSF-1–dependent increase in the abundance of chaperone mRNA. Moreover, in contrast to their deficient response to acute heat shock, gcy-8 worms showed chaperone induction in response to chronic (repeated or prolonged) heat shock. The authors thus propose that neuronal regulation of chaperone production enables C. elegans to respond differently to acute or chronic stress.

V. Prahlad, R. I. Morimoto, Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins. Proc. Natl. Acad. Sci. U.S.A. 108, 14204–14209 (2011). [Abstract] [Full Text]

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