Proteasomal inhibition induced by manganese ethylene-bis-dithiocarbamate: relevance to Parkinson's disease.
Maneb, a widely used fungicide, has been associated with Parkinsonism in humans. In experimental models, maneb and its major active element, manganese ethylene-bis-dithiocarbamate (Mn-EBDC) cause selective nigrostriatal neurodegeneration in mice and in rats, respectively. To investigate the mechanisms underlying this neurodegeneration, we studied the effects of Mn-EBDC on proteasomal function, which is decreased in patients with Parkinson's disease (PD), in a dopaminergic neuronal cell line (MES 23.5 or MES). The results demonstrated that exposure of MES cells to 6 microM Mn-EBDC for 7 days produced not only significant neurotoxicity but also inhibition of proteasomal chymotrypsin-like and postglutamyl peptidase activities. Proteasomal dysfunction was accompanied by formation of cytoplasmic inclusions that were positive for alpha-synuclein immunostaining and significantly increased sodium dodecyl sulfate-insoluble alpha-synuclein aggregation seen by Western blot analysis. In addition, there was a significant increase in oxidative stress, evidenced by elevated total protein carbonyl content, in cells treated with Mn-EBDC. Manipulation of intracellular reduced glutathione levels with N-acetyl-L-cysteine or L-buthionine sulfoximine pretreatment to modulate Mn-EBDC-mediated oxidative stress altered Mn-EBDC-mediated neurotoxicity, proteasomal dysfunction, and alpha-synuclein aggregation in these cells. These data suggest that neurotoxicity-induced by Mn-EBDC is at least partially attributable to Mn-EBDC-mediated proteasomal inhibition, and that the proteasome may be an important target by which environmental exposure modifies the risk for developing PD in vulnerable populations.
Zhou
Y
Y
Department of Pathology, Division of Neuropathology, University of Washington School of Medicine, Box 359635 Harborview Medical Center, Seattle 98104, USA.
Shie
F-S
FS
Piccardo
P
P
Montine
T J
TJ
Zhang
J
J
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D005028:Ethylenebis(dithiocarbamates) / Q000494:pharmacology*; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D061988:Proteasome Inhibitors; D011506:Proteins / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
D005028:Ethylenebis(dithiocarbamates); D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009942:Organometallic Compounds; D061988:Proteasome Inhibitors; D011506:Proteins; D051843:Synucleins; D051844:alpha-Synuclein; C471036:manganese ethylenebis(dithiocarbamate)