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J. Biol. Chem., Vol. 279, Issue 18, 19099-19112, April 30, 2004

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1-Methyl-4-phenylpyridinium-induced Apoptosis in Cerebellar Granule Neurons Is Mediated by Transferrin Receptor Iron-dependent Depletion of Tetrahydrobiopterin and Neuronal Nitric-oxide Synthase-derived Superoxide^*

Tiesong Shang, Srigiridhar Kotamraju, Shasi V. Kalivendi, Cecilia J. Hillard, and B. Kalyanaraman¶

From the Department of Biophysics and Free Radical Research Center and the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

In this study, we investigated the molecular mechanisms of toxicity of 1-methyl-4-phenylpyridinium (MPP⁺), an ultimate toxic metabolite of a mitochondrial neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that causes Parkinson-like symptoms in experimental animals and humans. We used rat cerebellar granule neurons as a model cell system for investigating MPP⁺ toxicity. Results show that MPP⁺ treatment resulted in the generation of reactive oxygen species from inhibition of complex I of the mitochondrial respiratory chain, and inactivation of aconitase. This, in turn, stimulated transferrin receptor (TfR)-dependent iron signaling via activation of the iron-regulatory protein/iron-responsive element interaction. MPP⁺ caused a time-dependent depletion of tetrahydrobiopterin (BH₄) that was mediated by H₂O₂ and transferrin iron. Depletion of BH₄ decreased the active, dimeric form of neuronal nitric-oxide synthase (nNOS). MPP⁺-mediated "uncoupling" of nNOS decreased ^.NO and increased superoxide formation. Pretreatment of cells with sepiapterin to promote BH₄ biosynthesis or cell-permeable iron chelator and TfR antibody to prevent iron-catalyzed BH₄ decomposition inhibited MPP⁺ cytotoxicity. Preincubation of cerebellar granule neurons with nNOS inhibitor exacerbated MPP⁺-induced iron uptake, BH₄ depletion, proteasomal inactivation, and apoptosis. We conclude that MPP⁺-dependent aconitase inactivation, Tf-iron uptake, and oxidant generation result in the depletion of intracellular BH₄, leading to the uncoupling of nNOS activity. This further exacerbates reactive oxygen species-mediated oxidative damage and apoptosis. Implications of these results in unraveling the molecular mechanisms of neurodegenerative diseases (Parkinson's and Alzheimer's disease) are discussed.

Received for publication, January 6, 2004 , and in revised form, January 28, 2004.

^* This work was supported by National Institutes of Health Grants NS39958 and IPOIHL68769-01 and by the Parson's Foundation. 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.

^¶ To whom correspondence should be addressed: Dept. of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Tel.: 414-456-4035; Fax: 414-156-6512; E-mail: balarama{at}mcw.edu.

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