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

ABSTRACT: Alzheimer's, Parkinson's and Huntington's disease 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 C. 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.

SUBMITTER: Dr. Rafael, Pascual Vazquez-Manrique

PROVIDER: S-SCDT-10_15252-EMBR_202255556 | biostudies-other |

REPOSITORIES: biostudies-other

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

Project description:Alzheimer’s, Parkinson’s or Huntington’s disease 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 and to investigate the mechanisms that protect against dysregulated homeostasis. We report that the protein UNC-1 activates neurohormonal signalling from the sulfotransferase SSU-1 in ASJ sensory/endocrine neurons. This hormone targets the nuclear receptor NHR-1, which acts cell-autonomously in the muscles to protect against 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 for the first time 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.

2022-12-12 | GSE220662 | GEO

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