Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila

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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.
Publisher
NATL ACAD SCIENCES
Issue Date
2005-07
Language
English
Article Type
Article
Keywords

UBIQUITIN-PROTEIN LIGASE; ALPHA-SYNUCLEIN; MPTP MODEL; DISEASE; MELANOGASTER; GENE; DEGRADATION; MUTATIONS; APOPTOSIS; STRESS

Citation

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.102, no.29, pp.10345 - 10350

ISSN
0027-8424
DOI
10.1073/pnas.0500346102
URI
http://hdl.handle.net/10203/6444
Appears in Collection
BS-Journal Papers(저널논문)
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