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

Abstract

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.

• Authors: Y Zhou, F-S Shie, P Piccardo, T J Montine, J Zhang
• Journal: Neuroscience (Neuroscience) Vol. 128 Issue 2 Pg. 281-91 ( 2004) ISSN: 0306-4522 [Print] United States
• PMID: 15350641 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Ethylenebis(dithiocarbamates)
• Nerve Tissue Proteins
• Neurotoxins
• Organometallic Compounds
• Proteasome Inhibitors
• Proteins
• Synucleins
• alpha-Synuclein
• manganese ethylenebis(dithiocarbamate)

Topics

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