Published online before print January 2, 2004, 10.1073/pnas.0307453101
PNAS | January 13, 2004 | vol. 101 | no. 2 | 665-670
pnas.org
NEUROSCIENCE
JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease
Stéphane Hunot * , Miquel Vila , Peter Teismann , Roger J. Davis ¶, Etienne C. Hirsch , Serge Przedborski ||, Pasko Rakic ** and Richard A. Flavell * ¶
*Section of Immunobiology, ¶Howard Hughes Medical Institute, and **Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06520; Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpêtrière, 75013 Paris, France; Departments of Neurology and ||Pathology and the Center for Neurobiology and Behavior, Columbia University, New York, NY 10032; and Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605
Contributed by Richard A. Flavell, November 10, 2003
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopamine-containing neurons, but the molecular pathways underlying its pathogenesis remain uncertain. Here, we show that by eliminating c-Jun N-terminal kinases (JNKs) we can prevent neurodegeneration and improve motor function in an animal model of PD. First, we found that c-Jun is activated in dopaminergic neurons from PD patients and in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model of PD. Examination of various JNK-deficient mice shows that both JNK2 and JNK3, but not JNK1, are required for MPTP-induced c-Jun activation and dopaminergic cell demise. Furthermore, we have identified cyclooxygenase (COX) 2 as a molecular target of JNK activation and demonstrated that COX-2 is indispensable for MPTP-induced dopaminergic cell death. Our data revealed that JNK2- and JNK3-induced COX-2 may be a principle pathway responsible for neurodegeneration in PD.
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Abbreviations: COX, cyclooxygenase; GFAP, glial fibrillary acidic protein; JNK, c-Jun N-terminal kinase; MAC-1, macrophage antigen complex 1; MPP+, 1-methyl-4-phenylpyridinium ion; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson's disease; SN, substantia nigra; SNpc, SN pars compacta; TH, tyrosine hydroxylase.
To whom correspondence should be addressed at: Yale University School of Medicine, The Anlyan Center S-569, 300 Cedar Street, New Haven, CT 06520. E-mail: richard.flavell@yale.edu. |
