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Blocking c-jun n-terminal kinase (jnk) translocation to the mitochondria prevents 6-hydroxydopamine-induced toxicity in vitro and in vivo

Academic Article
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Overview

authors

  • Chambers, J. W.
  • Howard, S.
  • LoGrasso, Philip

publication date

  • January 2013

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Because oxidative stress and mitochondrial dysfunction are well known contributors to Parkinson disease (PD), we set out to investigate the role mitochondrial JNK plays in the etiology of 6-hydroxydopamine-induced (6-OHDA) oxidative stress, mitochondrial dysfunction, and neurotoxicity in SHSY5Y cells and neuroprotection and motor behavioral protection in vivo. To do this, we utilized a cell-permeable peptide of the outer mitochondrial membrane protein, Sab (SH3BP5), as an inhibitor of JNK mitochondrial translocation. In vitro studies showed that 6-OHDA induced JNK translocation to the mitochondria and that inhibition of mitochondrial JNK signaling by Tat-Sab(KIM1) protected against 6-OHDA-induced oxidative stress, mitochondrial dysfunction, and neurotoxicity. Administration of Tat-Sab(KIM1) via an intracerebral injection into the mid-forebrain bundle increased the number of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta by 2-fold (p < 0.05) in animals lesioned with 6-OHDA, compared with animals treated only with 6-OHDA into the nigrostriatal pathway. In addition, Tat-Sab(KIM1) decreased the d-amphetamine-induced unilateral rotations associated with the lesion by 30% (p < 0.05). Steady-state brain levels of Tat-Sab(KIM1) at day 7 were 750 nm, which was ∼3.4-fold higher than the IC(50) for this peptide versus Sab protein. Collectively, these data suggest that 6-OHDA induced JNK translocation to the mitochondria and that blocking this translocation reduced oxidative stress, mitochondrial dysfunction, and neurotoxicity both in vitro and in vivo. Moreover, the data suggest that inhibitors that block association of JNKs with the mitochondria may be useful neuroprotective agents for the treatment of Parkinson disease.

subject areas

  • Animals
  • Blotting, Western
  • Cell Death
  • Cell Line
  • Dopamine
  • Gene Silencing
  • Humans
  • Immunohistochemistry
  • In Vitro Techniques
  • JNK Mitogen-Activated Protein Kinases
  • Mitochondria
  • Neurons
  • Oxidopamine
  • Protein Transport
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
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Identity

PubMed Central ID

  • PMC3542993

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M112.421354

PubMed ID

  • 23184940
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Additional Document Info

start page

  • 1079

end page

  • 1087

volume

  • 288

issue

  • 2

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