title: Phenazine derivatives cause proteotoxicity and stress in C. elegans.
abstract: It is widely recognized that bacterial metabolites have toxic effects in animal systems. Phenazines are a common bacterial metabolite within the redox-active exotoxin class. These compounds have been shown to be toxic to the soil invertebrate Caenorhabditis elegans with the capability of causing oxidative stress and lethality. Here we report that chronic, low-level exposure to three separate phenazine molecules (phenazine-1-carboxylic acid, pyocyanin and 1-hydroxyphenazine) upregulated ER stress response and enhanced expression of a superoxide dismutase reporter in vivo. Exposure to these molecules also increased protein misfolding of polyglutamine and α-synuclein in the bodywall muscle cells of C. elegans. Exposure of worms to these phenazines caused additional sensitivity in dopamine neurons expressing wild-type α-synuclein, indicating a possible defect in protein homeostasis. The addition of an anti-oxidant failed to rescue the neurotoxic and protein aggregation phenotypes caused by these compounds. Thus, increased production of superoxide radicals that occurs in whole animals in response to these phenazines appears independent from the toxicity phenotype observed. Collectively, these data provide cause for further consideration of the neurodegenerative impact of phenazines.
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487-0344, United States.
authors.forename: Arpita
authors.initials: A
authors.lastname: Ray
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487-0344, United States.
authors.forename: Courtney
authors.initials: C
authors.lastname: Rentas
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487-0344, United States.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487-0344, United States. Electronic address: kcaldwel@bama.ua.edu.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism; D017930:Genes, Reporter; D018384:Oxidative Stress; D010455:Peptides / Q000378:metabolism; D010619:Phenazines / Q000633:toxicity*; D017510:Protein Folding; D011710:Pyocyanine / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D010455:Peptides; D010619:Phenazines; D051844:alpha-Synuclein; C037165:1-phenazinecarboxylic acid; C097188:polyglutamine; C050093:1-hydroxyphenazine; D011710:Pyocyanine; D013482:Superoxide Dismutase
keywords: C. elegans; ER stress; Phenazines; Polyglutamine; α-Synuclein