Regulation of axotomy-induced dopaminergic neuron death and c-Jun phosphorylation by targeted inhibition of cdc42 or mixed lineage kinase
| Autor: | Wiplove R. Lamba, Patrice D. Smith, Shawn P. Hayley, Stephen J. Crocker, Matthew P. Mount, Ruth S. Slack, David S. Park, Steven M. Callaghan |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Male
MAP Kinase Kinase 4 medicine.medical_treatment Dopamine Substantia nigra Biochemistry Cellular and Molecular Neuroscience medicine Animals Enzyme Inhibitors Phosphorylation Rats Wistar Protein kinase A cdc42 GTP-Binding Protein Neurons MAP kinase kinase kinase biology Cell Death Pars compacta Kinase Dopaminergic JNK Mitogen-Activated Protein Kinases Medial Forebrain Bundle Axotomy MAP Kinase Kinase Kinases Rats Substantia Nigra nervous system Mitogen-activated protein kinase Gene Targeting Nerve Degeneration biology.protein Neuroscience |
| Zdroj: | Journal of neurochemistry. 96(2) |
| ISSN: | 0022-3042 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text