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A role for mixed lineage kinases in granule cell apoptosis induced by cytoskeletal disruption
Author(s) -
Müller Georg Johannes,
Geist Marie Aavang,
Veng Lone Merete,
Willesen Mette Georgi,
Johansen Flemming Fryd,
Leist Marcel,
Vaudano Elisabetta
Publication year - 2006
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/j.1471-4159.2005.03590.x
Subject(s) - apoptosis , microbiology and biotechnology , programmed cell death , kinase , colchicine , c jun , biology , neurite , neurotoxicity , chemistry , in vitro , biochemistry , toxicity , transcription factor , organic chemistry , gene , genetics
Microtubule disruption by colchicine induces apoptosis in selected neuronal populations. However, little is known about the upstream death signalling events mediating the neurotoxicity. We investigated first whether colchicine‐induced granule cell apoptosis activates the c‐Jun N‐terminal kinase (JNK) pathway. Cultured murine cerebellar granule cells were exposed to 1 µ m colchicine for 24 h. Activation of the JNK pathway was detected by western blotting as well as immunocytochemistry using antibodies against phospho‐c‐Jun (p‐c‐Jun). Next, adult male rats were injected intracerebroventricularly with colchicine (10 µg), and JNK pathway activation in dentate granule cells (DGCs) was detected by antibodies against p‐c‐Jun. The second part of the study tested the involvement of mixed lineage kinases (MLK) as upstream activators of the JNK pathway in colchicine toxicity, using CEP‐1347, a potent MLK inhibitor. In vitro , significant inhibition of the JNK pathway, activated by colchicine, was achieved by 100–300 n m CEP‐1347, which blocked both activation of cell death proteases and apoptosis. Moreover, CEP‐1347 markedly delayed neurite fragmentation and cell degeneration. In vivo , CEP‐1347 (1 mg/kg) significantly prevented p‐c‐jun increase following injection of colchicine, and enhanced survival of DGCs. We conclude that colchicine‐induced neuronal apoptosis involves the JNK/MLK pathway, and that protection of granule cells can be achieved by MLK inhibition.