Divergent Nodes of Non-autonomous UPRER Signaling through Serotonergic and Dopaminergic Neurons
Ryo Higuchi‐Sanabria, Jenni Durieux, Naame Kelet, Stefan Homentcovschi, Mattias de los Rios Rogers, Samira Monshietehadi, Gilberto Garcia, Sofia Dallarda, Joseph R. Daniele, Vidhya Ramachandran, Arushi Sahay, Sarah U. Tronnes, Larry Joe, Andrew Dillin
Abstract
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 the 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, whereas serotonergic neurons are sufficient to drive protein homeostasis in peripheral tissues. These signaling modalities are unique and independent and together coordinate the beneficial effects of neuronal cell non-autonomous ER stress signaling upon health and longevity.