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Regulation of axotomy‐induced dopaminergic neuron death and c‐Jun phosphorylation by targeted inhibition of cdc42 or mixed lineage kinase
Author(s) -
Crocker Stephen J.,
Hayley Shawn P.,
Smith Patrice D.,
Mount Matthew P.,
Lamba Wiplove R.,
Callaghan Steven M.,
Slack Ruth S.,
Park David S.
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.1471-4159.2005.03568.x
Subject(s) - axotomy , pars compacta , substantia nigra , dopaminergic , c jun , microbiology and biotechnology , biology , kinase , neuroscience , chemistry , dopamine , biochemistry , regeneration (biology) , gene , transcription factor
Mechanical transection of the nigrostriatal dopamine pathway at the medial forebrain bundle (MFB) results in the delayed degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). We have previously demonstrated that c‐Jun activation is an obligate component of neuronal death in this model. Here we identified the small GTPase, cdc42, and mixed lineage kinases (MLKs) as upstream factors regulating neuronal loss and activation of c‐Jun following MFB axotomy. Adenovirus‐mediated expression of a dominant‐negative form of cdc42 in nigral neurons blocked MFB axotomy‐induced activation (phosphorylation) of MAP kinase kinase 4 (MKK4) and c‐Jun, resulting in attenuation of SNpc neuronal death. Pharmacological inhibition of MLKs, MKK4‐activating kinases, significantly reduced the phosphorylation of c‐Jun and abrogated dopaminergic neuronal degeneration following MFB axotomy. Taken together, these findings suggest that death of nigral dopaminergic neurons following axotomy can be attenuated by targeting cell signaling events upstream of c‐Jun N‐terminal mitogen‐activated protein kinase/c‐Jun.