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

被引:347
作者
Hunot, S
Vila, M
Teismann, P
Davis, RJ
Hirsch, EC
Przedborski, S
Rakic, P
Flavell, RA
机构
[1] Yale Univ, Sch Med, Anlyan Ctr S 569, Immunobiol Sect, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA
[3] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06520 USA
[4] Hop La Pitie Salpetriere, Inst Natl Sante & Rech Med, U289, F-75013 Paris, France
[5] Columbia Univ, Dept Neurol, New York, NY 10032 USA
[6] Columbia Univ, Dept Pathol, New York, NY 10032 USA
[7] Columbia Univ, Ctr Neurobiol & Behav, New York, NY 10032 USA
[8] Univ Massachusetts, Sch Med, Dept Biochem & Mol Biol, Worcester, MA 01605 USA
关键词
D O I
10.1073/pnas.0307453101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:665 / 670
页数:6
相关论文
共 32 条
[1]   MECHANISMS OF EXCITOTOXICITY IN NEUROLOGIC DISEASES [J].
BEAL, MF .
FASEB JOURNAL, 1992, 6 (15) :3338-3344
[2]   Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation [J].
Behrens, A ;
Sibilia, M ;
Wagner, EF .
NATURE GENETICS, 1999, 21 (03) :326-329
[3]   c-Jun N-terminal protein kinase (JNK) 2/3 is specifically activated by stress, mediating c-Jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons [J].
Coffey, ET ;
Smiciene, G ;
Hongisto, V ;
Cao, J ;
Brecht, S ;
Herdegen, T ;
Courtney, MJ .
JOURNAL OF NEUROSCIENCE, 2002, 22 (11) :4335-4345
[4]   Parkinson's disease: Mechanisms and models [J].
Dauer, W ;
Przedborski, S .
NEURON, 2003, 39 (06) :889-909
[5]   Signal transduction by the JNK group of MAP kinases [J].
Davis, RJ .
CELL, 2000, 103 (02) :239-252
[6]  
Fahn S, 2000, MERRITTS NEUROLOGY, P679
[7]   SELECTIVE RETENTION OF MPP+ WITHIN THE MONOAMINERGIC SYSTEMS OF THE PRIMATE BRAIN FOLLOWING MPTP ADMINISTRATION - AN INVIVO AUTORADIOGRAPHIC STUDY [J].
HERKENHAM, M ;
LITTLE, MD ;
BANKIEWICZ, K ;
YANG, SC ;
MARKEY, SP ;
JOHANNESSEN, JN .
NEUROSCIENCE, 1991, 40 (01) :133-158
[8]   The c-Jun N-terminal kinases in cerebral microglia: immunological functions in the brain [J].
Hidding, U ;
Mielke, K ;
Waetzig, V ;
Brecht, S ;
Hanisch, U ;
Behrens, A ;
Wagner, E ;
Herdegen, T .
BIOCHEMICAL PHARMACOLOGY, 2002, 64 (5-6) :781-788
[9]   Nuclear translocation of NF-kappa B is increased in dopaminergic neurons of patients with Parkinson disease [J].
Hunot, S ;
Brugg, B ;
Ricard, D ;
Michel, PP ;
Muriel, MP ;
Ruberg, M ;
Faucheux, BA ;
Agid, Y ;
Hirsch, EC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (14) :7531-7536
[10]   TIME-COURSE AND MORPHOLOGY OF DOPAMINERGIC NEURONAL DEATH CAUSED BY THE NEUROTOXIN 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE [J].
JACKSONLEWIS, V ;
JAKOWEC, M ;
BURKE, RE ;
PRZEDBORSKI, S .
NEURODEGENERATION, 1995, 4 (03) :257-269