Abstract
Background Cellular mechanisms aimed at repairing protein damage and maintaining homeostasis, widely understood to be triggered by the damage itself, have recently been shown to be under cell nonautonomous control in the metazoan C elegans. The heat shock response (HSR) is one such conserved mechanism, activated by cells upon exposure to proteotoxic conditions such as heat. Previously, we had shown that this conserved cytoprotective response is regulated by the thermosensory neuronal circuitry of C elegans. Here, we investigate the mechanisms and physiological relevance of neuronal control. Results By combining optogenetic methods with live visualization of the dynamics of the heat shock transcription factor (HSF1), we show that excitation of the AFD thermosensory neurons is sufficient to activate HSF1 in another cell, even in the absence of temperature increase. Excitation of the AFD thermosensory neurons enhances serotonin release. Serotonin release elicited by direct optogenetic stimulation of serotonergic neurons activates HSF1 and upregulates molecular chaperones through the metabotropic serotonin receptor SER-1. Consequently, excitation of serotonergic neurons alone can suppress protein misfolding in C elegans peripheral tissue. Conclusions These studies imply that thermosensory activity coupled to serotonergic signaling is sufficient to activate the protective HSR prior to frank proteotoxic damage. The ability of neurosensory release of serotonin to control cellular stress responses and activate HSF1 has powerful implications for the treatment of protein conformation diseases.
Original language | English (US) |
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Pages (from-to) | 163-174 |
Number of pages | 12 |
Journal | Current Biology |
Volume | 25 |
Issue number | 2 |
DOIs | |
State | Published - Jan 19 2015 |
Funding
We would like to acknowledge the members of the V.P. laboratory, Jessica Nelson, Josh Weiner, Sarit Smolikove, Tali Gidalevitz, Anat Ben-Zvi, Michael Petrascheck, Sandra Encalada, and Daniel Colon-Ramos for helpful comments. The DCR186 strain was a kind gift from Daniel Colon-Ramos. Nematode strains were obtained from the CGC, funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). L.A.M.-V. was supported by the Diversity Supplement to NS057931 (Colón-Ramos/L.A.M.-V.). L.C. was funded by the Fulbright Franco-American Commission. R.I.M. was funded by grants from the NIH (NIGMS, NIA, NINDS), the Ellison Medical Foundation, and the Daniel F. and Ada L. Rice Foundation. V.P. was funded by the Ellison Medical Foundation (AG-NS-1056-13).
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
- General Agricultural and Biological Sciences