Proteasomal inhibition induced by manganese ethylene-bis-dithiocarbamate: relevance to Parkinson's disease

Y Zhou, F-S Shie, P Piccardo, T J Montine, J Zhang

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)281-91
Number of pages11
Issue number2
Publication statusPublished - 2004


  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Cell Line
  • Ethylenebis(dithiocarbamates)
  • Immunohistochemistry
  • Inclusion Bodies
  • Mesencephalon
  • Molecular Sequence Data
  • Nerve Tissue Proteins
  • Neurons
  • Neurotoxins
  • Organometallic Compounds
  • Oxidation-Reduction
  • Oxidative Stress
  • Parkinson Disease, Secondary
  • Proteasome Inhibitors
  • Proteins
  • Synucleins
  • alpha-Synuclein


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