In multicellular organisms, neurons integrate a diverse array of external cues to affect downstream changes in organismal health. Specifically, activation of the endoplasmic reticulum (ER) unfolded protein response (UPRER) in neurons increases lifespan by preventing age-onset loss of ER proteostasis and driving lipid depletion in a cell non-autonomous manner. The mechanism of this communication is dependent on release of small clear vesicles from neurons. We find dopaminergic neurons are necessary and sufficient for activation of cell non-autonomous UPRER to drive lipid depletion in peripheral tissues, while serotonergic neurons are necessary and sufficient to drive protein homeostasis in peripheral tissues. These signaling modalities are unique and independent, and together coordinate the benefits of neuronal cell non-autonomous ER stress signaling upon health and longevity.
Higuchi-Sanabria, Ryo and Durieux, Jenni and Kelet, Naame and Homentcovschi, Stefan and Monshietehadi, Samira and Garcia, Gilberto and Dallarda, Sofia and Daniele, Joseph R. and Ramachandran, Vidhya and Tronnes, Sarah U. and Joe, Larry and Dillin¹, Andrew, Divergent Nodes of Non-Autonomous UPR
ER Signaling Through Serotonergic and Dopaminergic Neurons. Available at SSRN: https://ssrn.com/abstract=3681991 or http://dx.doi.org/10.2139/ssrn.3681991
This version of the paper has not been formally peer reviewed.
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