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. 2004 Jan 13;101(2):665-70.
doi: 10.1073/pnas.0307453101. Epub 2004 Jan 2.

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

Stéphane Hunot  1 , Miquel Vila, Peter Teismann, Roger J Davis, Etienne C Hirsch, Serge Przedborski, Pasko Rakic, Richard A Flavell
Affiliations

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

Stéphane Hunot et al. Proc Natl Acad Sci U S A. .

Abstract

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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Figures

Fig. 1.
Fig. 1.
c-Jun is activated in dopaminergic neurons after MPTP intoxication. (A) Western blot analysis for phospho-c-Jun in the mouse mesencephalon after MPTP injections (arrow). Compared with saline-injected mice (S), the phospho-c-Jun expression level increases in a time-dependent manner after MPTP intoxication. Data represent mean ± SEM. (n = 3–5). *, P < 0.01, compared with saline-injected mice (two-tailed t test). (B–P) Double immunofluorescent staining for phospho-c-Jun (G–K), Nissl (B and C), TH (D), GFAP (E), or MAC-1 (F) on ventral midbrain tissue sections. The expression of phospho-c-Jun in the SN (arrowheads in B) was virtually absent in saline-injected mice (G) but increased greatly by 8 h after MPTP treatment (H Inset). At 12 h, phospho-c-Jun expression (H) was still elevated in neuronal cells (M) and translocated to the nucleus (M Inset is a higher magnification of the area in the dotted rectangle). Neurons displaying phospho-c-Jun immunoreactivity were positive for the dopaminergic cell-specific marker TH (N). Phospho-c-Jun staining never colocalized with the astrocytic marker GFAP (O) or the microglial cell marker MAC-1 (P). [Scale bar represents 60 μm (B, C, G, H, L, and M), 10 μm (D, I, and N), and 20 μm (H and M Insets).]
Fig. 2.
Fig. 2.
Immunohistochemical detection of c-Jun/AP-1 in transverse sections of control (A) and parkinsonian (B and C) SNpc. c-Jun immunoreactivity (arrows) was observed in perikarya and processes of dopaminergic neurons, identified by their neuromelamin content (arrowheads). (B and C) Note examples of melanized dopaminergic neuron displaying strong immunoreactivity in the nucleus (arrow), which can be distinguished clearly from neuromelanin pigments (arrowheads). [Scale bar represents 40 μm(A and B), 15 μm (B Inset), and 10 μm (C).]
Fig. 3.
Fig. 3.
Comparison of MPTP-induced nigrostriatal pathway injury in WT and Jnk–/– mice. (A) Peroxidase immunohistochemistry for TH on midbrain sections from saline- and MPTP-injected WT and JNK-deficient mice. (Scale bar represents 200 μm.) (B) Stereological counts of TH-positive cells in the SNpc at 7 days after MPTP intoxication. JNK2 or JNK3 ablation elicits sparing of TH-positive neurons after MPTP treatment, as compared with WT mice. Dual deletion of JNK2 and JNK3 increases the protective effect further. *, P < 0.01, compared with MPTP-injected WT mice (Mann–Whitney U test). (C and D) Motor performance of saline- or MPTP-treated WT and JNK-deficient mice measured on a Rotarod. The mean times on the rod recorded for increasing rod-rotation speeds (8–15 mice per group; C) and the mean overall rod performance (ORP, see Materials and Methods) for each group of mice (D) show that MPTP-intoxicated JNK-deficient animals display significant improvement of motor functions compared with MPTP-treated WT mice. *, P < 0.05, by Mann–Whitney U test.
Fig. 4.
Fig. 4.
Comparison of glial reaction and c-Jun activation in MPTP-intoxicated WT and JNK-knockout (KO) mice. (A) Immunohistochemical analysis for MAC-1 and GFAP indicates that MPTP-induced glial reaction is not altered in JNK-null mice as compared with WT animals. (Scale bar represents 300 μm.) (B) Western blot analysis for phospho-c-Jun expression in the mesencephalon after MPTP treatment shows that JNK2 and JNK3 are required for MPTP-induced c-Jun phosphorylation. Data represent mean ± SEM for three or four mice per group. *, P < 0.05; **, P < 0.01, compared with MPTP-treated WT mice (two-tailed t test).
Fig. 5.
Fig. 5.
JNK signaling pathway is required for COX-2 induction after neuronal noxious stress. (A) Expression of Cox-2 mRNA in the hippocampus of kainic acid-treated mice, as assayed by RT-PCR, is abolished in Jnk3-null mice. (B) Western blot analysis for COX-2 expression in the mesencephalon after MPTP treatment in WT mice for the indicated times. *, P < 0.01, compared with saline-injected mice. (C) MPTP-induced COX-2 expression in the mesencephalon is attenuated in JNK-deficient mice. *, P < 0.05; **, P < 0.01, compared with MPTP-treated WT mice (two-tailed t test). In B and C, data represent mean ± SEM for three or four mice per group. (D) Unlike COX-2 expression, COX-1 expression is not altered after MPTP treatment.
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