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

Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):665-70. doi: 10.1073/pnas.0307453101. Epub 2004 Jan 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Cyclooxygenase 2
  • DNA Primers
  • Disease Models, Animal
  • Immunohistochemistry
  • Isoenzymes / biosynthesis*
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Parkinson Disease / enzymology*
  • Parkinson Disease / pathology
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Reverse Transcriptase Polymerase Chain Reaction


  • DNA Primers
  • Isoenzymes
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases