The parkinsonian neurotoxin, MPP+ induces phosphorylated c-Jun in dopaminergric neurons of mesencephalic cultures.
The stress-activated protein kinase (SAPK) cascade serves a critical role in the apoptotic death of neuronal cells in response to a variety of cellular stresses. Recent in vitro and in vivo evidence has directly implicated this kinase in the death of dopaminergic nigral neurons in the MPTP model of Parkinson's disease (PD). To assess the involvement of c-Jun, a key transcription factor substrate of SAPK (also known as c-Jun N-terminal kinase, or JNK) in the MPTP-induced death of dopaminergic nigral neurons, we determined the ability of MPP+, the active toxin metabolite of MPTP, to induce the phosphorylated form of c-Jun in dopaminergic neurons in nigral (ventral mesencephalon) cultures. At a dose of MPP+ that specifically induces apoptotic changes in nuclear morphology in tyrosine hydroxylase-positive (dopaminergic) cells in these cultures, MPP+ induces nuclear phospho-c-Jun immunoreactivity (IR). The peak induction of phospho-c-Jun IR was observed 16h after beginning MPP+ exposure, and preceded the maximal induction of apoptotic nuclear changes by approximately 8h. These data support an important role for the SAPK/JNK pathway including its c-Jun transcriptional target in the apoptotic death of dopaminergic nigral neurons in the MPTP model of PD.
Gearan
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Laboratory of Molecular Neurobiology, Department of Neurology, Massachusetts General Hospital, CNY-6616, Bldg 149 13th Street, Charlestown 02129, USA.
Castillo
O A
OA
Schwarzschild
M A
MA
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents; D007150:Immunohistochemistry; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010302:Parkinson Disease, Secondary / Q000139:chemically induced*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015259:Dopamine Agents; D016755:Proto-Oncogene Proteins c-jun; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine