JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease

S. Hunot, M. Vila, Peter Teismann, R. J. Davis, E. C. Hirsch, S. Przedborski, P. Rakic, R. A. Flavell

Research output: Contribution to journalArticle

324 Citations (Scopus)

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of doparnine-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.

Original languageEnglish
Pages (from-to)665-670
Number of pages5
JournalPNAS
Volume101
Issue number2
Early online date2 Jan 2004
DOIs
Publication statusPublished - 13 Jan 2004

Keywords

  • NF-KAPPA-B
  • C-JUN
  • DOPAMINERGIC-NEURONS
  • INDUCED APOPTOSIS
  • GENE-EXPRESSION
  • MAP KINASES
  • MPTP MODEL
  • BRAIN
  • CELLS
  • PROTEIN

Cite this

Hunot, S., Vila, M., Teismann, P., Davis, R. J., Hirsch, E. C., Przedborski, S., ... Flavell, R. A. (2004). JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. PNAS, 101(2), 665-670. https://doi.org/10.1073/pnas.0307453101

JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. / Hunot, S.; Vila, M.; Teismann, Peter; Davis, R. J.; Hirsch, E. C.; Przedborski, S.; Rakic, P.; Flavell, R. A.

In: PNAS, Vol. 101, No. 2, 13.01.2004, p. 665-670.

Research output: Contribution to journalArticle

Hunot, S, Vila, M, Teismann, P, Davis, RJ, Hirsch, EC, Przedborski, S, Rakic, P & Flavell, RA 2004, 'JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease', PNAS, vol. 101, no. 2, pp. 665-670. https://doi.org/10.1073/pnas.0307453101
Hunot, S. ; Vila, M. ; Teismann, Peter ; Davis, R. J. ; Hirsch, E. C. ; Przedborski, S. ; Rakic, P. ; Flavell, R. A. / JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. In: PNAS. 2004 ; Vol. 101, No. 2. pp. 665-670.
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AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of doparnine-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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