Stress increases in exopher-mediated neuronal extrusion require lipid biosynthesis, FGF, and EGF RAS/MAPK signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 36; pp. 1 - 12
• Main Authors: Cooper, Jason F., Guasp, Ryan J., Arnold, Meghan Lee, Grant, Barth D., Driscoll, Monica
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.09.2021
• Subjects: Animals; Biological Sciences; Biosynthesis; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - metabolism; Epidermal growth factor; Epidermal Growth Factor - metabolism; Expulsion; Extrusion; Fasting; Fatty acids; Fatty-acid synthase; Fibroblast growth factors; Fibroblast Growth Factors - metabolism; Food availability; Forkhead protein; Genes, ras - genetics; Growth factors; Homeostasis; Lipids; Lipogenesis - physiology; MAP kinase; MAP Kinase Signaling System - physiology; Membrane vesicles; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurons; Neurons - metabolism; Neurotoxicity; Osmotic stress; Oxidation-Reduction; Peptide transporter; Proteins; Ras protein; Signal Transduction; Signaling; Stress, Physiological - physiology; Transcription factors; stress; MAP kinase; exopher; fasting; neurology
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2101410118

In human neurodegenerative diseases, neurons can transfer toxic protein aggregates to surrounding cells, promoting pathology via poorly understood mechanisms. In Caenorhabditis elegans, proteostressed neurons can expel neurotoxic proteins in large, membrane-bound vesicles called exophers. We investigated how specific stresses impact neuronal trash expulsion to show that neuronal exopher production can be markedly elevated by oxidative and osmotic stress. Unexpectedly, we also found that fasting dramatically increases exophergenesis. Mechanistic dissection focused on identifying nonautonomous factors that sense and activate the fasting-induced exopher response revealed that DAF16/FOXO-dependent and -independent processes are engaged. Fasting-induced exopher elevation requires the intestinal peptide transporter PEPT-1, lipid synthesis transcription factors Mediator complex MDT-15 and SBP-1/SREPB1, and fatty acid synthase FASN-1, implicating remotely initiated lipid signaling in neuronal trash elimination. A conserved fibroblast growth factor (FGF)/RAS/MAPK signaling pathway that acts downstream of, or in parallel to, lipid signaling also promotes fasting-induced neuronal exopher elevation. A germline-based epidermal growth factor (EGF) signal that acts through neurons is also required for exopher production. Our data define a nonautonomous network that links food availability changes to remote, and extreme, neuronal homeostasis responses relevant to aggregate transfer biology.