Ziram causes dopaminergic cell damage by inhibiting E1 ligase of the proteasome.
The etiology of Parkinson disease (PD) is unclear but may involve environmental toxins such as pesticides leading to dysfunction of the ubiquitin proteasome system (UPS). Here, we measured the relative toxicity of ziram (a UPS inhibitor) and analogs to dopaminergic neurons and examined the mechanism of cell death. UPS (26 S) activity was measured in cell lines after exposure to ziram and related compounds. Dimethyl- and diethyldithiocarbamates including ziram were potent UPS inhibitors. Primary ventral mesencephalic cultures were exposed to ziram, and cell toxicity was assessed by staining for tyrosine hydroxylase (TH) and NeuN antigen. Ziram caused a preferential damage to TH+ neurons and elevated alpha-synuclein levels but did not increase aggregate formation. Mechanistically, ziram altered UPS function through interfering with the targeting of substrates by inhibiting ubiquitin E1 ligase. Sodium dimethyldithiocarbamate administered to mice for 2 weeks resulted in persistent motor deficits and a mild reduction in striatal TH staining but no nigral cell loss. These results demonstrate that ziram causes selective dopaminergic cell damage in vitro by inhibiting an important degradative pathway implicated in the etiology of PD. Chronic exposure to widely used dithiocarbamate fungicides may contribute to the development of PD, and elucidation of its mechanism would identify a new potential therapeutic target.
Chou
Arthur P
AP
Department of Neurology, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
Maidment
Nigel
N
Klintenberg
Rebecka
R
Casida
John E
JE
Li
Sharon
S
Fitzmaurice
Arthur G
AG
Fernagut
Pierre-Olivier
PO
Mortazavi
Farzad
F
Chesselet
Marie-Francoise
MF
Bronstein
Jeff M
JM
D000818:Animals; D004125:Dimethyldithiocarbamate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005659:Fungicides, Industrial / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D015039:Ziram / Q000494:pharmacology*
D004125:Dimethyldithiocarbamate; D004791:Enzyme Inhibitors; D005659:Fungicides, Industrial; D015039:Ziram; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine