Open AccessStress increases in exopher-mediated neuronal extrusion require lipid biosynthesis, FGF, and EGF RAS/MAPK signaling
Author(s) -
Jason Cooper,
Ryan Guasp,
Meghan Lee Arnold,
Barth D. Grant,
Monica Driscoll
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2101410118
Subject(s) - fibroblast growth factor , mapk/erk pathway , biosynthesis , microbiology and biotechnology , epidermal growth factor , signal transduction , chemistry , biology , biochemistry , receptor , gene
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. ProteostressedCaenorhabditis 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.