Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans.
Parkinson's disease is a complex neurodegenerative disorder characterized by the death of brain dopamine neurons. In mammals, dopamine neuronal degeneration can be triggered through exposure to neurotoxins accumulated by the presynaptic dopamine transporter (DAT), including 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium. We have established a system for the pharmacological and genetic evaluation of neurotoxin-induced dopamine neuronal death in Caenorhabditis elegans. Brief (1 h) exposure of green fluorescent protein-tagged, living worms to 6-OHDA causes selective degeneration of dopamine neurons. We demonstrate that agents that interfere with DAT function protect against 6-OHDA toxicity. 6-OHDA-triggered neural degeneration does not require the CED-3/CED-4 cell death pathway, but is abolished by the genetic disruption of the C. elegans DAT.
Nass
Richard
R
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6420, USA.
Hall
David H
DH
Miller
David M
DM
Blakely
Randy D
RD
D000818:Animals; D019556:COS Cells / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002522:Chlorocebus aethiops; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D015801:Helminth Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000235:genetics; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology*; D016627:Oxidopamine / Q000378:metabolism / Q000494:pharmacology*
D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; C089224:Ced-4 protein, C elegans; D050483:Dopamine Plasma Membrane Transport Proteins; D015801:Helminth Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D016627:Oxidopamine; D020169:Caspases; C089223:ced-3 protein, C elegans; D004298:Dopamine