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

Autores de IIS La Fe

• Ana Pilar Gómez Escribano

  Autor

• Marta Isabel Roca Marugán

  Autor

• Joaquin Javier Panadero Romero

  Autor

• María Dolores Sequedo Pérez

  Autor

• Juan Andres Burguera Hernandez

  Autor

• 

  Agustín Gerardo Lahoz Rodríguez

  Autor

• Rafael Vázquez Manrique

  Autor

Participantes ajenos a IIS La Fe

• Mora-Martínez, C
• Walker, DS
• Saini, R
• Knölker, HJ
• Blanca, J
• Cañizares, J
• Millán, JM
• Burton, NO
• Schafer, WR

Grupos

• 

  Biomedicina Molecular, Celular y Genómica

• Unidad de Biomarcadores y Medicina de Precisión (UBYMP)

Abstract

Alzheimer's, Parkinson's and Huntington's diseases can be caused by mutations that enhance protein aggregation, but we still do not know enough about the molecular players of these pathways to develop treatments for these devastating diseases. Here, we screen for mutations that might enhance aggregation in Caenorhabditis elegans, to investigate the mechanisms that protect against dysregulated homeostasis. We report that the stomatin homologue UNC-1 activates neurohormonal signalling from the sulfotransferase SSU-1 in ASJ sensory/endocrine neurons. A putative hormone, produced in ASJ, targets the nuclear receptor NHR-1, which acts cell autonomously in the muscles to modulate polyglutamine repeat (polyQ) aggregation. A second nuclear receptor, DAF-12, functions oppositely to NHR-1 to maintain protein homeostasis. Transcriptomics analyses of unc-1 mutants revealed changes in the expression of genes involved in fat metabolism, suggesting that fat metabolism changes, controlled by neurohormonal signalling, contribute to protein homeostasis. Furthermore, the enzymes involved in the identified signalling pathway are potential targets for treating neurodegenerative diseases caused by disrupted protein homeostasis.

Keywords

• Caenorhabditis elegans; fat metabolism; nuclear receptors; protein aggregation; steroid hormone signalling