Open AccessTrimethylamine modulates dauer formation, neurodegeneration, and lifespan through tyra‐3/daf‐11 signaling in Caenorhabditis elegans
Author(s) -
Khanna Amit,
Sellegounder Durai,
Kumar Jitendra,
Chamoli Manish,
Vargas Miguel,
Chinta Shankar J.,
Rane Anand,
Nelson Christopher,
Peiris T. Harshani,
Brem Rachel,
Andersen Julie,
Lithgow Gordon,
Kapahi Pankaj
Publication year - 2021
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13351
Subject(s) - biology , caenorhabditis elegans , neurodegeneration , signal transduction , g protein coupled receptor , trimethylamine n oxide , microbiome , microbiology and biotechnology , receptor , trimethylamine , genetics , biochemistry , disease , gene , medicine , pathology
In the nematode Caenorhabditis elegans , signals derived from bacteria in the diet, the animal's major nutrient source, can modulate both behavior and healthspan. Here we describe a dual role for trimethylamine (TMA), a human gut flora metabolite, which acts as a nutrient signal and a neurotoxin. TMA and its associated metabolites are produced by the human gut microbiome and have been suggested to serve as risk biomarkers for diabetes and cardiovascular diseases. We demonstrate that the tyramine receptor TYRA‐3, a conserved G protein‐coupled receptor (GPCR), is required to sense TMA and mediate its responses. TMA activates guanylyl cyclase DAF‐11 signaling through TYRA‐3 in amphid neurons (ASK) and ciliated neurons (BAG) to mediate food‐sensing behavior. Bacterial mutants deficient in TMA production enhance dauer formation, extend lifespan, and are less preferred as a food source. Increased levels of TMA lead to neural damage in models of Parkinson's disease and shorten lifespan. Our results reveal conserved signaling pathways modulated by TMA in C. elegans that are likely to be relevant for its effects in mammalian systems.