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MPTP activates ASK1-p38 MAPK signaling pathway through TNF-dependent Trx1 oxidation in parkinsonism mouse model

Ajit Ray1, Neha Sehgal2, Smitha Karunakaran2

  • 1National Brain Research Centre, Nainwal Mode, Manesar-122051, India; Centre for Neuroscience, Indian Institute of Science, Bangalore 560012, India.

Free Radical Biology & Medicine
|July 13, 2015
PubMed

Insights

Parkinson's disease involves neuron death via the apoptosis signal-regulating kinase 1 (ASK1)-p38 MAPK pathway. Blocking tumor necrosis factor (TNF) early prevents this activation, offering potential neuroprotection.

Area of Science:

  • Neuroscience
  • Cell Signaling
  • Molecular Biology

Background:

  • The apoptosis signal-regulating kinase 1 (ASK1)-p38 MAPK signaling cascade is linked to dopaminergic neuron death in Parkinson's disease (PD).
  • Understanding the upstream activators of ASK1 is crucial for developing neuroprotective strategies against PD.

Purpose of the Study:

  • To investigate the upstream activators of ASK1 in a mouse model of parkinsonism.
  • To elucidate the temporal cascade of death signaling in the ventral midbrain (VMB) and striatum (ST) following MPTP exposure.
  • To assess the role of tumor necrosis factor (TNF) in activating the ASK1 pathway.

Main Methods:

  • Utilized the MPTP mouse model to induce parkinsonism and analyzed protein activation and interactions in VMB and striatum.
  • Employed protein thiol oxidation assays to examine thioredoxin 1 (Trx1) and glutathione-S-transferase µ 1 (GSTM1) status.
  • Applied protein covariation network analysis (PCNA) to map signaling pathways and used TNF-neutralizing antibodies to block TNF signaling.

Main Results:

  • MPTP selectively activated ASK1 and p38 MAPK in the VMB through thioredoxin 1 (Trx1) oxidation, releasing its inhibition of ASK1.
  • Early increases in tumor necrosis factor (TNF) in the VMB preceded Trx1 oxidation and ASK1-p38 MAPK activation.
  • Intrathecal administration of TNF-neutralizing antibodies blocked MPTP-induced Trx1 oxidation and subsequent ASK1-p38 MAPK activation.

Conclusions:

  • Early intervention to block TNF signaling can prevent protein thiol oxidation and the activation of the ASK1-p38 MAPK death pathway, suggesting a critical neuroprotective target in PD.
  • Protein covariation network analysis is a valuable tool for understanding complex cause-and-effect relationships within signaling networks in diseases like PD.
Keywords:
Cell deathGraph theoryNeurodegenerationOxidative stressThiols

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