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

Area of Science:

• Cell Biology
• Neuroscience
• Genetics

Background:

• Neurons can transfer toxic protein aggregates in neurodegenerative diseases.
• The mechanisms of this aggregate transfer are poorly understood.
• In C. elegans, neurons expel toxic proteins via exophers.

Purpose of the Study:

• Investigate how specific stresses affect neuronal trash expulsion.
• Identify nonautonomous factors regulating fasting-induced exopher production.

Main Methods:

• Utilized C. elegans as a model organism.
• Applied oxidative, osmotic, and fasting stresses.
• Conducted mechanistic dissection of signaling pathways.

Main Results:

• Oxidative and osmotic stress, and particularly fasting, increase exopher production.
• Fasting-induced exophergenesis involves DAF16/FOXO-dependent and -independent pathways.
• Requires intestinal peptide transporter PEPT-1, lipid synthesis factors (MDT-15, SBP-1), and fatty acid synthase FASN-1.
• Involves FGF/RAS/MAPK and germline-based EGF signaling pathways.

Conclusions:

• Defined a nonautonomous network linking food availability to neuronal homeostasis.
• Demonstrated the role of lipid and growth factor signaling in neuronal trash elimination.
• Provided insights into aggregate transfer relevant to neurodegenerative diseases.