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Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins

Author:
Prahlad, Veena, Morimoto, Richard I.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2011 v.108 no.34 pp. 14204-14209
ISSN:
0027-8424
Subject:
Caenorhabditis elegans, animals, heat stress, human diseases, molecular chaperones, mutants, myocytes, neurons, neurosecretion, protein aggregates, protein conformation, quality control, toxicity
Abstract:
The consequence of chronic protein misfolding is the basis of many human diseases. To combat the deleterious effects of accumulated protein damage, all cells possess robust quality-control systems, specifically molecular chaperones and clearance machineries, that sense and respond to protein misfolding. However, for many protein conformational diseases, it is unclear why this quality-control system does not efficiently counter protein aggregation. Previous findings that the heat shock response in Caenorhabditis elegans is regulated by thermosensory neurons led us to consider whether neuronal activity could also be responsible for the inadequate response of an organism to chronic protein misfolding. Here we show, in animals expressing polyglutamine expansion proteins and mutant SOD-1G93A in intestinal or muscle cells, that the nervous system does indeed control the cellular response to misfolded proteins. Whereas polyglutamine expansion-expressing animals with WT thermosensory neurons readily express protein aggregates, leading to cellular dysfunction without concomitant up-regulation of molecular chaperones, modulation of the nervous system results in chaperone up-regulation that suppresses aggregation and toxicity. The neuronal signal is transmitted through calcium-activated dense core vesicle neurosecretion. Cell-nonautonomous control of chaperone expression by the thermosensory neurons allows C. elegans to respond differently to acute stress such as heat shock, and chronic stress caused by the expression of misfolded proteins, suggesting that neuronal signaling determines the course of cellular proteotoxicity.
Agid:
209842