Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death-associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson's disease: protection by alpha-lipoic acid

FASEB J. 2007 Jul;21(9):2226-36. doi: 10.1096/fj.06-7580com. Epub 2007 Mar 16.

Abstract

Parkinson's disease (PD), a neurodegenerative disorder, causes severe motor impairment due to loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). MPTP, a neurotoxin that causes dopaminergic cell loss in mice, was used in an animal model to study the pathogenic mechanisms leading to neurodegeneration. We observed the activation of apoptosis signal regulating kinase (ASK1, MAPKKK) and phosphorylation of its downstream targets MKK4 and JNK, 12 h after administration of a single dose of MPTP. Further, Daxx, the death-associated protein, translocated to the cytosol selectively in SNpc neurons seemingly due to MPTP mediated down-regulation of DJ-1, the redox-sensitive protein that binds Daxx in the nucleus. Coadministration of alpha-lipoic acid (ALA), a thiol antioxidant, abolished the activation of ASK1 and phosphorylation of downstream kinases, MKK4, and JNK and prevented the down-regulation of DJ-1 and translocation of Daxx to the cytosol seen after MPTP. ALA also attenuated dopaminergic cell loss in SNpc seen after subchronic MPTP treatment. Our studies demonstrate for the first time that MPTP triggers death signaling pathway by activating ASK1 and translocating Daxx, in vivo, in dopaminergic neurons in SNpc of mice and thiol antioxidants, such as ALA terminate this cascade and afford neuroprotection.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacokinetics
  • Acetylcysteine / pharmacology
  • Alkynes / pharmacology
  • Animals
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use*
  • Antiparkinson Agents / pharmacology
  • Antiparkinson Agents / therapeutic use*
  • Biotransformation
  • Carrier Proteins / metabolism*
  • Cell Nucleus / metabolism
  • Co-Repressor Proteins
  • Cystathionine gamma-Lyase / antagonists & inhibitors
  • Cytosol / metabolism
  • Dopamine / analysis
  • Drug Evaluation, Preclinical
  • Electron Transport Complex I / drug effects
  • Enzyme Activation / drug effects
  • Glutathione / analysis
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • MAP Kinase Signaling System / drug effects*
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / metabolism
  • Male
  • Mesencephalon / chemistry
  • Mice
  • Mice, Inbred C57BL
  • Molecular Chaperones
  • Nerve Tissue Proteins / metabolism*
  • Neurons / chemistry
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins / biosynthesis
  • Oncogene Proteins / genetics
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / metabolism
  • Peroxiredoxins
  • Phosphorylation
  • Protein Deglycase DJ-1
  • Protein Processing, Post-Translational / drug effects
  • Protein Transport / drug effects
  • Substantia Nigra / drug effects*
  • Substantia Nigra / metabolism
  • Thioctic Acid / pharmacology
  • Thioctic Acid / therapeutic use*

Substances

  • Alkynes
  • Antioxidants
  • Antiparkinson Agents
  • Carrier Proteins
  • Co-Repressor Proteins
  • Daxx protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Nuclear Proteins
  • Oncogene Proteins
  • propargylglycine
  • Thioctic Acid
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Peroxiredoxins
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • Map3k5 protein, mouse
  • MAP Kinase Kinase 4
  • Map2k4 protein, mouse
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1
  • Cystathionine gamma-Lyase
  • Electron Transport Complex I
  • Glutathione
  • Glycine
  • Dopamine
  • Acetylcysteine