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Bacterially produced metabolites protect C. elegans neurons from degeneration

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dc.citation.titlePLoS Biology
dc.citation.volume18
dc.creatorUrrutia, Arles
dc.creatorGarcia Angulo, Victor Antonio
dc.creatorFuentes, Andrés
dc.creatorCaneo, Mauricio
dc.creatorLegüe, Marcela
dc.creatorUrquiza Zurich, Sebastian
dc.creatorDelgado, Scarlett E
dc.creatorUgalde, Juan
dc.creatorBurdisso, Paula
dc.creatorCalixto, Andrea
dc.date.accessioned2024-05-03T14:43:48Z
dc.date.available2024-05-03T14:43:48Z
dc.date.issued2020-03-24
dc.description.abstractCaenorhabditis elegans and its cognate bacterial diet comprise a reliable, widespread model to study diet and microbiota effects on host physiology. Nonetheless, how diet influences the rate at which neurons die remains largely unknown. A number of models have been used in C. elegans as surrogates for neurodegeneration. One of these is a C. elegans strain expressing a neurotoxic allele of the mechanosensory abnormality protein 4 (MEC-4d) degenerin/epithelial Na+ (DEG/ENaC) channel, which causes the progressive degeneration of the touch receptor neurons (TRNs). Using this model, our study evaluated the effect of various dietary bacteria on neurodegeneration dynamics. Although degeneration of TRNs was steady and completed at adulthood in the strain routinely used for C. elegans maintenance (Escherichia coli OP50), it was significantly reduced in environmental and other laboratory bacterial strains. Strikingly, neuroprotection reached more than 40% in the E. coli HT115 strain. HT115 protection was long lasting well into old age of animals and was not restricted to the TRNs. Small amounts of HT115 on OP50 bacteria as well as UV-killed HT115 were still sufficient to produce neuroprotection. Early growth of worms in HT115 protected neurons from degeneration during later growth in OP50. HT115 diet promoted the nuclear translocation of DAF-16 (ortholog of the FOXO family of transcription factors), a phenomenon previously reported to underlie neuroprotection caused by down-regulation of the insulin receptor in this system. Moreover, a daf-16 loss-of-function mutation abolishes HT115-driven neuroprotection. Comparative genomics, transcriptomics, and metabolomics approaches pinpointed the neurotransmitter γ-aminobutyric acid (GABA) and lactate as metabolites differentially produced between E. coli HT115 and OP50. HT115 mutant lacking glutamate decarboxylase enzyme genes (gad), which catalyze the conversion of GABA from glutamate, lost the ability to produce GABA and also to stop neurodegeneration. Moreover, in situ GABA supplementation or heterologous expression of glutamate decarboxylase in E. coli OP50 conferred neuroprotective activity to this strain. Specific C. elegans GABA transporters and receptors were required for full HT115-mediated neuroprotection. Additionally, lactate supplementation also increased anterior ventral microtubule (AVM) neuron survival in OP50. Together, these results demonstrate that bacterially produced GABA and other metabolites exert an effect of neuroprotection in the host, highlighting the role of neuroactive compounds of the diet in nervous system homeostasis.
dc.description.filFil: Urrutia, Arles. Universidad de Valparaíso. Facultad de Ciencias. Centro Interdisciplinario de Neurociencia de Valparaíso; Chile.
dc.description.filFil: Urrutia, Arles. Universidad Mayor. Facultad de Ciencias. Centro de Genómica y Bioinformática; Chile.
dc.description.filFil: Garcia Angulo, Victor Antonio. Universidad Mayor. Facultad de Ciencias. Centro de Genómica y Bioinformática; Chile.
dc.description.filFil: Garcia Angulo, Victor Antonio. Universidad de Chile. Facultad de Medicina. Instituto de Ciencias Biomédicas; Chile.
dc.description.filFil: Fuentes, Andrés. Universidad Mayor. Facultad de Ciencias. Centro de Genómica y Bioinformática; Chile.
dc.description.filFil: Caneo, Mauricio. Universidad de Valparaíso. Facultad de Ciencias. Centro Interdisciplinario de Neurociencia de Valparaíso; Chile.
dc.description.filFil: Caneo, Mauricio. Universidad Mayor. Facultad de Ciencias. Centro de Genómica y Bioinformática; Chile.
dc.description.filFil: Legüe, Marcela. Universidad de Valparaíso. Facultad de Ciencias. Centro Interdisciplinario de Neurociencia de Valparaíso; Chile.
dc.description.filFil: Legüe, Marcela. Universidad Mayor. Facultad de Ciencias. Centro de Genómica y Bioinformática; Chile.
dc.description.filFil: Urquiza Zurich, Sebastian. Universidad Mayor. Facultad de Ciencias. Centro de Genómica y Bioinformática; Chile.
dc.description.filFil: Delgado, Scarlett. Universidad de Valparaíso. Facultad de Ciencias. Centro Interdisciplinario de Neurociencia de Valparaíso; Chile.
dc.description.filFil: Delgado, Scarlett E. Universidad Mayor. Facultad de Ciencias. Centro de Genómica y Bioinformática; Chile.
dc.description.filFil: Ugalde, Juan. Universidad Mayor. Facultad de Ciencias. Centro de Genómica y Bioinformática; Chile.
dc.description.filFil: Burdisso, Paula. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Consejo Nacional de Investigaciones Científicas y Técnicas. Plataforma Argentina de Biología Estructural y Metabolómica. Instituto de Biología Molecular y Celular de Rosario (CONICET-PLABEM-IBR); Argentina.
dc.description.filFil: Calixto, Andrea. Universidad de Valparaíso. Facultad de Ciencias. Centro Interdisciplinario de Neurociencia de Valparaíso; Chile.
dc.description.sponsorshipMillennium Scientific Initiative of the Chilean Ministry of Economy, Development, and Tourism: P029-022-F
dc.description.sponsorshipApoyo Redes Formación de Centros: REDES180138, P918PTE 3
dc.description.sponsorshipFondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT): 1181089
dc.format.extent1-31
dc.identifier.issn1545-7885
dc.identifier.urihttps://hdl.handle.net/2133/26978
dc.language.isoen
dc.publisherPublic Library of Science
dc.relation.publisherversionhttps://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000638
dc.relation.publisherversionhttps://doi.org/10.1371/journal.pbio.3000638
dc.rightsopenAccess
dc.rights.holderUniversidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas
dc.rights.textAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAge factors
dc.subjectGlutamate decarboxylase
dc.subjectMechanoreceptors
dc.subjectNeuroprotective agents
dc.subjectGamma-aminobutyric acid
dc.subjectGamma-aminobutyric acid
dc.titleBacterially produced metabolites protect C. elegans neurons from degeneration
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

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