Changes in lipid metabolism driven by steroid signalling modulate proteostasis in C. elegans

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mutations enhancing protein aggregation are implicated in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's.
• Understanding the molecular mechanisms of protein homeostasis is crucial for developing effective treatments.
• Current knowledge of protective pathways against dysregulated homeostasis remains incomplete.

Purpose of the Study:

• To screen for mutations affecting protein aggregation in Caenorhabditis elegans.
• To investigate molecular players and pathways that protect against dysregulated protein homeostasis.
• To identify potential therapeutic targets for neurodegenerative diseases.

Main Methods:

• Screening for mutations in Caenorhabditis elegans.
• Investigating neurohormonal signaling pathways involving UNC-1, SSU-1, NHR-1, and DAF-12.
• Utilizing transcriptomics analysis of unc-1 mutants.

Main Results:

• Identified a novel neurohormonal signaling pathway where UNC-1 activates SSU-1 in ASJ neurons.
• Discovered that a hormone from ASJ targets nuclear receptor NHR-1 in muscles to modulate polyglutamine repeat (polyQ) aggregation.
• Found that nuclear receptor DAF-12 opposes NHR-1 in maintaining protein homeostasis.
• Transcriptomics revealed that UNC-1 mutations alter genes involved in fat metabolism, linking it to protein homeostasis.

Conclusions:

• Neurohormonal signaling, influenced by fat metabolism, plays a role in maintaining protein homeostasis.
• The identified signaling pathway, including UNC-1, SSU-1, NHR-1, and DAF-12, is critical for preventing protein aggregation.
• Enzymes within this pathway represent promising therapeutic targets for neurodegenerative diseases associated with protein misfolding and aggregation.