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J. Biol. Chem., Vol. 283, Issue 6, 3357-3364, February 8, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/6/3357    most recent M708451200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fei, Q. Articles by Ethell, D. W. Search for Related Content PubMed PubMed Citation Articles by Fei, Q. Articles by Ethell, D. W. Social Bookmarking                      What's this?

Paraquat Neurotoxicity Is Mediated by a Bak-dependent Mechanism^*

Qingyan Fei, Alison L. McCormack, Donato A. Di Monte, and Douglas W. Ethell¹

From the Division of Biomedical Sciences, University of California, Riverside, California 92521 and the Parkinson's Institute, Sunnyvale, California 94085

Paraquat (PQ) causes selective degeneration of dopaminergic neurons in the substantia nigra pars compacta, reproducing an important pathological feature of Parkinson disease. Oxidative stress, c-Jun N-terminal kinase activation, and -synuclein aggregation are each induced by PQ, but details of the cell death mechanisms involved remain unclear. We have identified a Bak-dependent cell death mechanism that is required for PQ-induced neurotoxicity. PQ induced morphological and biochemical features that were consistent with apoptosis, including dose-dependent cytochrome c release, with subsequent caspase-3 and poly(ADP-ribose) polymerase cleavage. Changes in nuclear morphology and loss of viability were blocked by cycloheximide, caspase inhibitor, and Bcl-2 overexpression. Evaluation of Bcl-2 family members showed that PQ induced high levels of Bak, Bid, BNip3, and Noxa. Small interfering RNA-mediated knockdown of BNip3, Noxa, and Bak each protected cells from PQ, but Bax knockdown did not. Finally, we tested the sensitivity of Bak-deficient mice and found them to be resistant to PQ treatments that depleted tyrosine hydroxylase immuno-positive neurons in the substantia nigra pars compacta of wild-type mice.

Received for publication, October 11, 2007 , and in revised form, December 3, 2007.

^* This work was supported by the National Institutes of Health (to D. A. D.) and by University of California, Riverside (to D. W. E.). 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 supplemental Figs. S1–S4.

¹ To whom correspondence should be addressed: B1621 Computer Stats Bldg., UC Riverside, 900 University Ave., Riverside, CA 92521-0121. Fax: 951-827-2496; E-mail: doug.ethell{at}ucr.edu.

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