title: Selenium induces cholinergic motor neuron degeneration in Caenorhabditis elegans.
abstract: Selenium is an essential micronutrient required for cellular antioxidant systems, yet at higher doses it induces oxidative stress. Additionally, in vertebrates environmental exposures to toxic levels of selenium can cause paralysis and death. Here we show that selenium-induced oxidative stress leads to decreased cholinergic signaling and degeneration of cholinergic neurons required for movement and egg-laying in Caenorhabditis elegans. Exposure to high levels of selenium leads to proteolysis of a soluble muscle protein through mechanisms suppressible by two pharmacological agents, levamisole and aldicarb which enhance cholinergic signaling in muscle. In addition, animals with reduction-of-function mutations in genes encoding post-synaptic levamisole-sensitive acetylcholine receptor subunits or the vesicular acetylcholine transporter developed impaired forward movement faster during selenium-exposure than normal animals, again confirming that selenium reduces cholinergic signaling. Finally, the antioxidant reduced glutathione, inhibits selenium-induced reductions in egg-laying through a cellular protective mechanism dependent on the C. elegans glutaredoxin, GLRX-21. These studies provide evidence that the environmental toxicant selenium induces neurodegeneration of cholinergic neurons through depletion of glutathione, a mechanism linked to the neuropathology of Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.
authors.affiliation: Department of Neurology, University of Arizona, Tucson, AZ 85724-5023, USA. aestevez@email.arizona.edu
authors.forename: Annette O
authors.initials: AO
authors.lastname: Estevez
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Mueller
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Morgan
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Szewczyk
authors.forename: Luke
authors.initials: L
authors.lastname: Teece
authors.forename: Antonio
authors.initials: A
authors.lastname: Miranda-Vizuete
authors.forename: Miguel
authors.initials: M
authors.lastname: Estevez
mesh_terms: D000199:Actins / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000633:toxicity*; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D002452:Cell Count; D059329:Cholinergic Neurons / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005697:Galactosides / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D007978:Levamisole / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009068:Movement / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D009132:Muscles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology*; D010243:Paralysis / Q000139:chemically induced; D011950:Receptors, Cholinergic / Q000235:genetics; D012098:Reproduction / Q000187:drug effects / Q000235:genetics; D012643:Selenium / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics
chemical_list: D000199:Actins; D000276:Adjuvants, Immunologic; D000975:Antioxidants; D029742:Caenorhabditis elegans Proteins; D005697:Galactosides; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D050494:Vesicular Acetylcholine Transport Proteins; C007816:beta-galactoside; D049452:Green Fluorescent Proteins; D007978:Levamisole; D005978:Glutathione; D012643:Selenium