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J. Biol. Chem., Vol. 280, Issue 52, 42655-42668, December 30, 2005
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Similar Patterns of Mitochondrial Vulnerability and Rescue Induced by Genetic Modification of 
-Synuclein, Parkin, and DJ-1 in Caenorhabditis elegans*
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2
From the
Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118-2526, Cambria Biosciences, Woburn, Massachusetts 01801, ||Hoffmann-La Roche, Basel CH4070, Switzerland, ¶Neurology Institute, College of Physicians and Surgeons, Columbia University, New York, New York 10032, **Centro de Patogenese Molecular, Faculty of Pharmacy, University of Lisbon, Av. das Forcas Armadas, Lisbon 1600-083, Portugal, the Department of Biological Science, University of Illinois, Chicago, Illinois 60607, and the Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455
How genetic and environmental factors interact in Parkinson disease is poorly understood. We have now compared the patterns of vulnerability and rescue of Caenorhabditis elegans with genetic modifications of three different genetic factors implicated in Parkinson disease (PD). We observed that expressing 
-synuclein, deleting parkin (K08E3.7), or knocking down DJ-1 (B0432.2) or parkin produces similar patterns of pharmacological vulnerability and rescue. C. elegans lines with these genetic changes were more vulnerable than nontransgenic nematodes to mitochondrial complex I inhibitors, including rotenone, fenperoximate, pyridaben, or stigmatellin. In contrast, the genetic manipulations did not increase sensitivity to paraquat, sodium azide, divalent metal ions (Fe(II) or Cu(II)), or etoposide compared with the nontransgenic nematodes. Each of the PD-related lines was also partially rescued by the antioxidant probucol, the mitochondrial complex II activator, D-
-hydroxybutyrate, or the anti-apoptotic bile acid tauroursodeoxycholic acid. Complete protection in all lines was achieved by combining D--hydroxybutyrate with tauroursodeoxycholic acid but not with probucol. These results show that diverse PD-related genetic modifications disrupt the mitochondrial function in C. elegans, and they raise the possibility that mitochondrial disruption is a pathway shared in common by many types of familial PD.
Received for publication, May 31, 2005 , and in revised form, October 18, 2005.
* This work was supported in part by National Institutes of Health Grants NS41786 and AG/NS17485 and United States Army Medical Research Command Grant 17-01-1-0781. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains Figs. S1–S4.
1 Both authors contributed equally to this work.
2 To whom correspondence should be addressed: Dept. of Pharmacology, Boston University School of Medicine, 715 Albany St., Rm. R614, Boston, MA 02118-2526. Tel.: 617-414-2652; Fax: 617-414-2651; E-mail: bwolozin{at}bu.edu.
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