期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：36
DOI：10.1073/pnas.2101410118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
In neurodegenerative disease, protein aggregates spread to neighboring cells to promote pathology. The in vivo regulation of toxic material transfer remains poorly understood, although mechanistic understanding should reveal previously unrecognized therapeutic targets. Proteostressed
Caenorhabditis elegans neurons can concentrate protein aggregates and extrude them in membrane-encased vesicles called exophers. We identify specific systemic stress conditions that enhance exopher production, revealing stress-type, stress-level, and temporal constraints on the process. We identify three pathways that promote fasting-induced exophergenesis: lipid synthesis, FGF/RAS/MAPK, and EGF/RAS/MAPK. In establishing an initial molecular model for transtissue requirements for fasting-induced exopher elevation in neurons, we report molecular insights into the regulation of aggregate transfer biology, relevant to the fundamental mysteries of neurodegenerative disease.
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.
