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c-Abl-p38α signaling plays an important role in MPTP-induced neuronal death

R Wu1,2, H Chen1,3, J Ma1,2

  • 1State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.

Cell Death and Differentiation
|October 31, 2015
PubMed

Insights

Oxidative stress contributes to Parkinson's disease (PD). Targeting the c-Abl and p38α signaling pathway may offer a new therapeutic strategy for PD by protecting neuronal cells.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Oxidative stress is a key factor in sporadic Parkinson's disease (PD) pathogenesis.
  • Neuronal cell death is a hallmark of PD, leading to motor deficits.

Purpose of the Study:

  • To investigate the role of c-Abl in oxidative stress-induced neuronal cell death in Parkinson's disease.
  • To identify downstream targets of c-Abl involved in PD pathology.

Main Methods:

  • Utilized a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) induced mouse model of acute Parkinson's disease.
  • Employed conditional knockout of c-Abl in neurons and pharmacological inhibition with STI571.
  • Applied Stable Isotope Labeling with Amino acids in Cell culture (SILAC) combined with biochemical assays to identify protein interactions and modifications.

Main Results:

  • c-Abl kinase was activated in the MPTP-induced PD model.
  • Inhibition or knockout of c-Abl protected dopaminergic neurons and improved motor function in MPTP-treated mice.
  • Identified p38α as a critical substrate of c-Abl, with c-Abl-mediated phosphorylation essential for p38α dimerization.
  • Inhibition of p38α also ameliorated neuronal loss in the PD model.

Conclusions:

  • The c-Abl-p38α signaling pathway is implicated in oxidative stress-induced dopaminergic neuron death in Parkinson's disease.
  • Targeting the c-Abl-p38α axis presents a potential therapeutic strategy for Parkinson's disease.

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