期刊
LABORATORY INVESTIGATION
卷 90, 期 2, 页码 156-167出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/labinvest.2009.124
关键词
JNKs; Tat-JBD; JIP-1; neuronal death; dopaminergic neuron
资金
- National Program of Basic Research of China [2006CB500706, 2007CB947900]
- National Natural Science Fundation of China [30872729, 30770732]
- Shanghai Pujiang Program [08PJ1407900]
- Shanghai Key Discipline Program [S30202]
- Science and Technology Commission of Shanghai [07DJ14005]
- Program for Outstanding Medical Academic Leader [LJ 06003]
Increasing evidence suggests that apoptosis may be the mechanism underlying cell death in selective loss of nigral dopaminergic neurons in Parkinson's disease (PD). Previous studies strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway has a critical role in the animal model with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. In this study, we report the inhibitory effect of a peptide designated as Tat-JBD on JNKs activation. The sequence of Tat is corresponding to the cell-membrane transduction domain of human immunodeficiency virus-type 1 (HIV-1) and the sequence of an 11-amino acid peptide is corresponding to the residues of JNK-binding domain (JBD) on JNK-interacting protein-1 (JIP-1). Tat-JBD is confirmed to perturb the assembly of JIP-1-JNKs complex, inhibit the activation of JNKs induced by MPTP and consequently diminish the phosphorylation of c-Jun. It also inhibits the phosphorylation of Bcl-2 and the releasing of Bax from Bcl-2/Bax dimmers, sequentially attenuates the translocation of Bax to mitochondria, the release of cytochrome c, the activation of caspase3 and the hydrolyzation of poly-ADP-ribose-polymerase. The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by infusion of the peptide Tat-JBD in MPTP-treated mice. Our findings imply that Tat-JBD offers neuroprotection against MPTP injury via inhibiting the JNK-signaling pathway, and may provide a promising therapeutic approach for PD. Laboratory Investigation (2010) 90, 156-167; doi:10.1038/labinvest.2009.124; published online 14 December 2009
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