Small peptide inhibitor of JNKs protects against MPTP-induced nigral dopaminergic injury via inhibiting the JNK-signaling pathway.
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.
Pan
Jing
J
Institute of Health Science, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Qian
Jing
J
Zhang
Yu
Y
Ma
Jianfang
J
Wang
Gang
G
Xiao
Qin
Q
Chen
Shengdi
S
Ding
Jianqing
J
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects*; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology*; D010455:Peptides / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000627:therapeutic use
D048868:Adaptor Proteins, Signal Transducing; C490665:Mapk8ip protein, mouse; D018696:Neuroprotective Agents; D010455:Peptides; D047428:Protein Kinase Inhibitors; C548497:Tat-JBD peptide; D054322:tat Gene Products, Human Immunodeficiency Virus; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D048031:JNK Mitogen-Activated Protein Kinases