Small peptide inhibitor of JNK3 protects dopaminergic neurons from MPTP induced injury via inhibiting the ASK1-JNK3 signaling pathway

PLoS One. 2015 Apr 9;10(4):e0119204. doi: 10.1371/journal.pone.0119204. eCollection 2015.

Abstract

Introduction and aims: The ASK1-JNK3 signaling pathway plays a pivotal role in the pathogenesis of Parkinson's disease (PD). The specific binding of β-arrestin2 to JNK3 is essential for activation of the ASK1-JNK3 cascade, representing a potential therapeutic target for preventing dopaminergic neuronal death in PD. The aim of this study was to identify a novel strategy for the prevention of dopaminergic neuronal death in PD.

Methods: Based on the specific binding of β-arrestin2 to JNK3, a 21-amino-acid fusion peptide, termed JNK3-N-Tat, was synthesized. We evaluated the ability of this peptide to inhibit the binding of β-arrestin2 to its target domain in JNK3 in vitro and in vivo.

Results: The JNK3-N-Tat peptide inhibited activation of the ASK1-JNK3 cascade by disrupting the interaction between β-arrestin2 and JNK3. JNK3-N-Tat exerted beneficial effects through pathways downstream of JNK3 and improved mitochondrial function, resulting in attenuated MPP+/MPTP-induced damage. JNK3-N-Tat protected mesencephalic dopaminergic neurons against MPTP-induced toxicity.

Conclusions: JNK3-N-Tat, a JNK3-inhibitory peptide, protects dopaminergic neurons against MPP+/MPTP-induced injury by inhibiting the ASK1-JNK3 signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / adverse effects*
  • Amino Acid Sequence
  • Animals
  • Apoptosis / drug effects
  • Arrestins / chemistry
  • Arrestins / metabolism
  • Cell Line, Tumor
  • Cytoprotection / drug effects
  • Dopaminergic Neurons / cytology*
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Humans
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / pathology
  • Mitogen-Activated Protein Kinase 10 / chemistry
  • Mitogen-Activated Protein Kinase 10 / metabolism*
  • Molecular Sequence Data
  • Parkinson Disease / pathology
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Signal Transduction / drug effects*
  • beta-Arrestins

Substances

  • Arrestins
  • Peptides
  • Protein Kinase Inhibitors
  • beta-Arrestins
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Mitogen-Activated Protein Kinase 10
  • MAP Kinase Kinase Kinase 5

Grants and funding

This study was supported by grants from National Key Program of Basic Research (2011CB504104) of China, the National Natural Science Foundation of China (81430022, 81371407, 81371409, 30900454). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.