Reference - Detail
|Author||Estevez AO, Mueller CL, Morgan KL, Szewczyk NJ, Teece L, Miranda-Vizuete A, Estevez M.|
|Title||Selenium induces cholinergic motor neuron degeneration in Caenorhabditis elegans.|
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.
|MeSH||Actins / metabolism Adjuvants, Immunologic / pharmacology Analysis of Variance Animals Animals, Genetically Modified Antioxidants / toxicity* Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics Cell Count Cholinergic Neurons / drug effects* Dose-Response Relationship, Drug Galactosides / metabolism Glutathione / metabolism Green Fluorescent Proteins / genetics Levamisole / pharmacology Motor Neurons* / drug effects Motor Neurons* / metabolism Motor Neurons* / pathology Movement / drug effects Muscle Proteins / metabolism Muscles / drug effects Muscles / metabolism Muscles / pathology Mutation / genetics Nerve Degeneration / chemically induced* Nerve Degeneration / pathology* Paralysis / chemically induced Receptors, Cholinergic / genetics Reproduction / drug effects Reproduction / genetics Selenium / toxicity* Signal Transduction / drug effects Vesicular Acetylcholine Transport Proteins / genetics|
|WOS Category||PHARMACOLOGY & PHARMACY TOXICOLOGY NEUROSCIENCES|