Cell non-autonomous control of autophagy and metabolism by glial cells.

Glia are the protectors of the nervous system, providing neurons with support and protection from cytotoxic insults. We previously discovered that four astrocyte-like glia can regulate organismal proteostasis and longevity in C. elegans. Expression of the UPRER transcription factor, XBP-1s, in these glia increases stress resistance, and longevity, and activates the UPRER in intestinal cells via neuropeptides. Autophagy, a key regulator of metabolism and aging, has been described as a cell autonomous process. Surprisingly, we find that glial XBP-1s enhances proteostasis and longevity by cell non-autonomously reprogramming organismal lipid metabolism and activating autophagy. Glial XBP-1s regulates the activation of another transcription factor, HLH-30/TFEB, in the intestine. HLH-30 activates intestinal autophagy, increases intestinal lipid catabolism, and upregulates a robust transcriptional program. Our study reveals a novel role for glia in regulating peripheral lipid metabolism, autophagy, and organellar health through peripheral activation of HLH-30 and autophagy.

Glia detect and mount a protective response to loss of dendrite substructure integrity in C. elegans.

Neurons have elaborate structures that determine their connectivity and functions. Changes in neuronal structure accompany learning and memory formation and are hallmarks of neurological disease. Here we show that glia monitor dendrite structure and respond to dendrite perturbation. In C. elegans mutants with defective sensory-organ dendrite cilia, adjacent glia accumulate extracellular matrix-laden vesicles, secrete excess matrix around cilia, alter gene expression, and change their secreted protein repertoire. Inducible cilia disruption reveals that this response is acute. DGS-1, a 7-transmembrane domain neuronal protein, and FIG-1, a multifunctional thrombospondin-domain glial protein, are required for glial detection of cilia integrity, and exhibit mutually-dependent localization to and around cilia, respectively. While inhibiting glial secretion disrupts dendritic cilia properties, hyperactivating the glial response protects against dendrite damage. Our studies uncover a homeostatic protective dendrite-glia interaction and suggest that similar signaling occurs at other sensory structures and at synapses, which resemble sensory organs in architecture and molecules.