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The Journal of Neuroscience, November 19, 2008, 28(47):12500-12509; doi:10.1523/JNEUROSCI.4511-08.2008

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Neurobiology of Disease
Selective Activation of p38 Mitogen-Activated Protein Kinase in Dopaminergic Neurons of Substantia Nigra Leads to Nuclear Translocation of p53 in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Mice

Smitha Karunakaran, Uzma Saeed, Mamata Mishra, R. Khader Valli, Shanker Datt Joshi, Durga Praveen Meka, Pankaj Seth, and Vijayalakshmi Ravindranath

Division of Molecular and Cellular Neurosciences, National Brain Research Centre, Nainwal Mode, Manesar 122050, India

Correspondence should be addressed to Vijayalakshmi Ravindranath, National Brain Research Centre, Nainwal Mode, Manesar 122050, India. Email: vijir{at}nbrc.ac.in

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Activation of the mixed lineage kinase and c-Jun N-terminal kinase (JNK) has been reported in models of PD. Our focus was to discern whether distinct pathways were activated in cell-specific manner within the SNpc. We now demonstrate the selective phosphorylation of p38 MAP kinase within the dopaminergic neurons, whereas JNK activation occurs predominantly in the microglia. p38 activation results in downstream phosphorylation of p53 and increased p53 mediated transcription of Bax and Puma in the ventral midbrain. Treatment with p38 inhibitor, SB239063 protected primary dopaminergic neurons derived from human progenitor cells from MPP⁺ mediated cell death and prevented the downstream phosphorylation of p53 and its translocation to the nucleus in vivo, in the ventral midbrain. The increased staining of phosphorylated p38 in the surviving neurons of SNpc in human brain sections from patients with PD and in MPTP treated mice but not in the ventral tegmental area provides further evidence suggesting a role for p38 in the degeneration of dopaminergic neurons of SNpc. We thus demonstrate the cell specific activation of MAP kinase pathways within the SNpc after MPTP treatment emphasizing the role of multiple signaling cascades in the pathogenesis and progression of the disease. Selective inhibitors of p38 may therefore, help preserve the surviving neurons in PD and slow down the disease progression.

Key words: Parkinson's disease; cell death; Bax; oxidative stress; MAP kinase; neurodegeneration

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Received Sept. 20, 2008; accepted Oct. 8, 2008.

Correspondence should be addressed to Vijayalakshmi Ravindranath, National Brain Research Centre, Nainwal Mode, Manesar 122050, India. Email: vijir{at}nbrc.ac.in

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