Regulation of axotomy-induced dopaminergic neuron death and c-Jun phosphorylation by targeted inhibition of cdc42 or mixed lineage kinase.
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.
Crocker
Stephen J
SJ
Neuroscience Research Institute, University of Ottawa and Ottawa Health Research Institute, Ottawa, Ontario, Canada.
Hayley
Shawn P
SP
Smith
Patrice D
PD
Mount
Matthew P
MP
Lamba
Wiplove R
WR
Callaghan
Steven M
SM
Slack
Ruth S
RS
Park
David S
DS
D000818:Animals; D019771:Axotomy; D016923:Cell Death; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018390:Gene Targeting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D008474:Medial Forebrain Bundle / Q000473:pathology / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D004298:Dopamine; D004791:Enzyme Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D020764:cdc42 GTP-Binding Protein; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11