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Valproic acid induces neuronal cell death through a novel calpain‐dependent necroptosis pathway
Author(s) -
Bollino Dominique,
Balan Irina,
Aurelian Laure
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13029
Subject(s) - necroptosis , xiap , histone deacetylase inhibitor , calpain , programmed cell death , microbiology and biotechnology , histone deacetylase , biology , caspase , inhibitor of apoptosis , apoptosis , phosphorylation , signal transduction , histone deacetylase 5 , kinase , histone , chemistry , biochemistry , enzyme , gene
A growing body of evidence indicates that valproic acid ( VPA ), a histone deacetylase inhibitor used to treat epilepsy and mood disorders, has histone deacetylase‐related and ‐unrelated neurotoxic activity, the mechanism of which is still poorly understood. We report that VPA induces neuronal cell death through an atypical calpain‐dependent necroptosis pathway that initiates with downstream activation of c‐Jun N‐terminal kinase 1 ( JNK 1) and increased expression of receptor‐interacting protein 1 ( RIP ‐1) and is accompanied by cleavage and mitochondrial release/nuclear translocation of apoptosis‐inducing factor, mitochondrial release of Smac/ DIABLO , and inhibition of the anti‐apoptotic protein X‐linked inhibitor of apoptosis ( XIAP ). Coinciding with apoptosis‐inducing factor nuclear translocation, VPA induces phosphorylation of the necroptosis‐associated histone H2A family member H2 AX , which is known to contribute to lethal DNA degradation. These signals are inhibited in neuronal cells that express constitutively activated MEK / ERK and/or PI 3‐K/Akt survival pathways, allowing them to resist VPA ‐induced cell death. The data indicate that VPA has neurotoxic activity and identify a novel calpain‐dependent necroptosis pathway that includes JNK 1 activation and RIP ‐1 expression.A growing body of evidence indicates that valproic acid (VPA) has neurotoxic activity, the mechanism of which is still poorly understood. We report, for the first time, that VPA activates a previously unrecognized calpain‐dependent necroptosis cascade that initiates with JNK1 activation and involves AIF cleavage/nuclear translocation and H2AX phosphorylation as well as an altered Smac/DIABLO to XIAP balance.