Divergent nodes of non-autonomous UPRER signaling through serotonergic and dopaminergic neurons Part II

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 beneficial effects of neuronal cell non-autonomous ER stress signaling upon health and longevity.

在多细胞生物体内，神经元整合多样化的外源性信号，以调控机体健康的下游生物学改变。具体而言，神经元内的内质网（endoplasmic reticulum, ER）未折叠蛋白反应（endoplasmic reticulum unfolded protein response, UPRER）被激活后，可通过阻止年龄相关性内质网蛋白质稳态丧失，并以细胞非自主方式诱导脂质耗竭，从而延长生物体寿命。该跨细胞通讯的机制依赖于神经元释放小型清亮囊泡。本研究发现，多巴胺能神经元是激活细胞非自主UPRER、诱导外周组织脂质耗竭的充要条件；而血清素能神经元则是调控外周组织蛋白质稳态的充要条件。这两类信号通路具有独特性且相互独立，二者协同介导神经元细胞非自主内质网应激信号对机体健康与寿命的有益作用。