Ziram Causes Dopaminergic Cell Damage by Inhibiting E1 Ligase of the Proteasome

Arthur P. Chou, Nigel Maidment, Rebecka Klintenberg, John E. Casida, Sharon Li, Arthur G. Fitzmaurice, Pierre-Olivier Fernagut, Farzad Mortazavi, Marie-Francoise Chesselet, Jeff M. Bronstein
Journal of Biological Chemistry. 2008-12-01; 283(50): 34696-34703
DOI: 10.1074/jbc.m802210200

1. J Biol Chem. 2008 Dec 12;283(50):34696-703. doi: 10.1074/jbc.M802210200. Epub
2008 Sep 25.

Ziram causes dopaminergic cell damage by inhibiting E1 ligase of the proteasome.

Chou AP(1), Maidment N, Klintenberg R, Casida JE, Li S, Fitzmaurice AG, Fernagut
PO, Mortazavi F, Chesselet MF, Bronstein JM.

Author information:
(1)Department of Neurology, University of California at Los Angeles, David
Geffen School of Medicine, Los Angeles, CA 90095, USA.

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.