Divergent Nodes of Non-autonomous UPRER Signaling through Serotonergic and Dopaminergic Neurons

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. [Display omitted] •Non-autonomous signaling of UPRER is mediated by serotonergic and dopaminergic neurons•Serotonergic neurons drive protein homeostasis to extend lifespan•Dopaminergic neurons drive lipid homeostasis to extend lifespan Higuchi-Sanabria et al. identify two distinct neuronal populations that are critical in signaling non-autonomous UPRER from neurons to the periphery: serotonergic neurons drive induction of protein changes and dopaminergic neurons drive induction of lipid changes.