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

Abstract : 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 $\mu$-calpain and was prevented by calpain inhibitors. 4) $\mu$-Calpain produced a loss of the DEVDase (Asp-Glu-Val-Asp) activity of active caspase-3. 5) Western blot analysis and experiments with $^{35}$S-radiolabeled caspase-3 showed that $\mu$-calpain cleaved the p20 subunit of active caspase-3 near its catalytic site. 6) $\mu$-Calpain activity was selectively inhibited (IC$_{50}$ of 100 $\mu$M) 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.
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Nicolas Bizat, Jean-Michel Hermel, Sandrine Humbert, Carine Jacquard, Christophe Créminon, et al.. $In\ Vivo$ Calpain/Caspase Cross-talk during 3-Nitropropionic Acid-induced Striatal Degeneration. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2003, 278 (44), pp.43245-43253. ⟨10.1074/jbc.M305057200⟩. ⟨cea-02290633⟩

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