Antiapoptotic and trophic effects of dominant-negative forms of dual leucine zipper kinase in dopamine neurons of the substantia nigra in vivo.
There is extensive evidence that the mitogen-activated protein kinase (MAPK) signaling cascade mediates programmed cell death in neurons. However, current evidence that the mixed linage kinases (MLKs), upstream in this cascade, mediate cell death is based, in the in vivo context, entirely on pharmacological approaches. The compounds used in these studies have neither complete specificity nor selectivity among these kinases. Therefore, to better address the molecular specificity of the MLKs in mediating neuron death, we used dominant-negative constructs delivered by AAV (adenoassociated virus) vector transfer. We assessed effects in a neurotoxin model of parkinsonism, in which neuroprotection by pharmacologic MLK inhibition has been reported. We find that two dominant-negative forms of dual leucine zipper kinase (DLK) inhibit apoptosis and enhance long-term survival of dopamine neurons, but a dominant negative of MLK3 does not. Interestingly, the kinase-dead form of DLK not only blocks apoptosis but also has trophic effects on dopamine neurons. Although the MAPK cascade activates a number of downstream cell death mediators, we find that inhibition of DLK correlates closely with blockade of phosphorylation of c-jun and prevention of cell death. We conclude that DLK acts primarily through c-jun phosphorylation to mediate cell death in this model.
Chen
Xiqun
X
Department of Neurology, The College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Rzhetskaya
Margarita
M
Kareva
Tatyana
T
Bland
Ross
R
During
Matthew J
MJ
Tank
A William
AW
Kholodilov
Nikolai
N
Burke
Robert E
RE
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D002227:Carbazoles / Q000627:therapeutic use; D000229:Dependovirus / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D016350:Leucine Zippers; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D010455:Peptides / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013378:Substantia Nigra / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D009842:Oligopeptides; D010455:Peptides; D049452:Green Fluorescent Proteins; C106592:3,9-bis((ethylthio)methyl)-K-252a; D016627:Oxidopamine; C085706:FLAG peptide; D014446:Tyrosine 3-Monooxygenase; D020928:Mitogen-Activated Protein Kinases; D010751:Phosphopyruvate Hydratase