( Parkinson''s disease | ubiquitination | tyrosine hydroxylase | degeneration | apoptosis )
Guang-Ho Cha *, Sunhong Kim *, Jeehye Park *, Eunji Lee *, Myungjin Kim *, Sung Bae Lee *, Jin Man Kim , Jongkyeong Chung *, and Kyoung Sang Cho *
*National Creative Research Initiatives Center for Cell Growth Regulation, and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-dong, Yusong-gu, Taejon 305-701, Korea; and Department of Pathology, Chungnam National University School of Medicine, 640 Daesa-dong, Chung-gu, Taejon 301-721, Korea
Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA, and approved May 23, 2005 (received for review January 14, 2005)
Parkin, an E3 ubiquitin ligase, has been found to be responsible for autosomal recessive juvenile parkinsonism characterized primarily by selective loss of dopaminergic neurons with subsequent defects in movements. However, the molecular mechanisms underlying this neuron loss remain elusive. Here, we characterized Drosophila parkin loss-of-function mutants, which exhibit shrinkage of dopaminergic neurons with decreased tyrosine hydroxylase level and impaired locomotion. The behavioral defect of parkin mutant flies was partially restored by administering L-DOPA, and the dopamine level in the brains of parkin mutant flies was highly decreased. Intriguingly, we found that c-Jun N-terminal kinase (JNK) is strongly activated in the dopaminergic neurons of parkin mutants and that impaired dopaminergic neuron phenotypes are dependent on the activation of the JNK signaling pathway. In consistent with this, our epistatic analysis and mammalian cell studies showed that Parkin inhibits the JNK signaling pathway in an E3 activity-dependent manner. These results suggest that loss of Parkin function up-regulates the JNK signaling pathway, which may contribute to the vulnerability of dopaminergic neurons in Drosophila parkin mutants and perhaps autosomal recessive juvenile parkinsonism patients.
Author contributions: G.-H.C., S.K., J.P., J.C., and K.S.C. designed research; G.-H.C., S.K., J.P., E.L., M.K., S.B.L., J.M.K., and K.S.C. performed research; G.-H.C., S.K., J.P., and J.C. analyzed data; and G.-H.C., S.K., J.P., and J.C. wrote the paper.
G.-H.C., S.K., and J.P. contributed equally to this work.
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