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J. Biol. Chem., Vol. 278, Issue 44, 43245-43253, October 31, 2003

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In Vivo Calpain/Caspase Cross-talk during 3-Nitropropionic Acid-induced Striatal Degeneration

IMPLICATION OF A CALPAIN-MEDIATED CLEAVAGE OF ACTIVE CASPASE-3^*

Nicolas Bizat, Jean-Michel Hermel, Sandrine Humbert¶||, Carine Jacquard, Christophe Créminon**, Carole Escartin, Frédéric Saudou¶||, Stan Krajewski, Philippe Hantraye¶¶, and Emmanuel Brouillet||||

From the Unité de Recherche Associée Commissariat à l'Energie Atomique (CEA)-CNRS 2210, Service Hospitalier Frédéric Joliot, Département de Recherches Médicales (DRM), Direction des Sciences du Vivant (DSV), Commissariat à l'Energie Atomique, 91401 Orsay Cedex, France, ^¶UMR 146 CNRS/Institut Curie, 91405 Orsay, France, ^**CEA, Service de Pharmacologie et Immunologie, DRM, DSV, CEN Saclay, 91191 Gif-sur-Yvette Cedex, France, Program on Cell Death and Apoptosis, The Burnham Institute, Program on Apoptosis, Cell Death and Aging, La Jolla, California 92037, and ^¶¶Isotopic Imaging, Biochemical and Pharmaceutical Unit (U2IBP), Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 91401 Orsay Cedex, France

The role of caspases and calpains in neurodegeneration remains unclear. In this study, we focused on these proteases in a rat model of Huntington's disease using the mitochondrial toxin 3-nitropropionic acid (3NP). Results showed that 3NP-induced death of striatal neurons was preceded by cytochrome c redistribution, transient caspase-9 processing, and activation of calpain, whereas levels of the active/processed form of caspase-3 remained low and were even reduced as compared with control animals. We evidenced here that this decrease in active caspase-3 levels could be attributed to calpain activation. Several observations supported this conclusion. 1) Pharmacological blockade of calpain in 3NP-treated rats increased the levels of endogenous processed caspase-9 and caspase-3. 2) Cell-free extracts prepared from the striatum of 3NP-treated rats degraded in vitro the p34 and p20 subunits of active recombinant caspase-9 and caspase-3, respectively. 3) This degradation of p34 and p20 could be mimicked by purified µ-calpain and was prevented by calpain inhibitors. 4) µ-Calpain produced a loss of the DEVDase (Asp-Glu-Val-Asp) activity of active caspase-3. 5) Western blot analysis and experiments with ³⁵S-radiolabeled caspase-3 showed that µ-calpain cleaved the p20 subunit of active caspase-3 near its catalytic site. 6) µ-Calpain activity was selectively inhibited (IC₅₀ of 100 µM) by a 12 amino acid peptide corresponding to the C terminus of p20. Our results showed that calpain can down-regulate the caspase-9/caspase-3 cell death pathway during neurodegeneration due to chronic mitochondrial defects in vivo and that this effect may involve, at least in part, direct cleavage of the caspase-3 p20 subunit.

Received for publication, May 14, 2003 , and in revised form, July 31, 2003.

^* This work was supported by CEA and CNRS and National Institutes of Health Grant NS36821 (to S. K.). 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.

Both authors contributed equally to this work.

^|| Investigators from INSERM.

An EMBO Young Investigator.

^|||| To whom correspondence should be addressed. Tel.: 33-1-69-86-78-15; Fax: 33-1-69-86-77-45; E-mail: brouille{at}shfj.cea.fr.

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