Molecular Neurobiology

, Volume 49, Issue 2, pp 1102–1116

c-Abl Tyrosine Kinase Mediates Neurotoxic Prion Peptide-Induced Neuronal Apoptosis via Regulating Mitochondrial Homeostasis

  • Bo Pan
  • Lifeng Yang
  • Jin Wang
  • Yunsheng Wang
  • Jihong Wang
  • Xiangmei Zhou
  • Xiaomin Yin
  • Zhongqiu Zhang
  • Deming Zhao
Article

DOI: 10.1007/s12035-014-8646-4

Cite this article as:
Pan, B., Yang, L., Wang, J. et al. Mol Neurobiol (2014) 49: 1102. doi:10.1007/s12035-014-8646-4

Abstract

Prion diseases are neurodegenerative disorders characterized by the accumulation of a disease-associated prion protein and apoptotic neuronal death. Previous studies indicated that the ubiquitous expression of c-Abl tyrosine kinase transduces a variety of extrinsic and intrinsic cellular signals. In this study, we demonstrated that a synthetic neurotoxic prion fragment (PrP106-126) activated c-Abl tyrosine kinase, which in turn triggered the upregulation of MST1 and BIM, suggesting the activation of the c-Abl-BIM signaling pathway. The peptide fragment was found to result in cell death via mitochondrial dysfunction in neuron cultures. Knockdown of c-Abl using small interfering RNA protected neuronal cells from PrP106-126-induced mitochondrial dysfunction, production of reactive oxygen species, and apoptotic events inducing translocation of Bax to the mitochondria, cytochrome c release into the cytosol, and activation of caspase-9 and caspase-3. Blocking the c-Abl tyrosine kinase also prevented neuronal cells from PrP106-126-induced apoptotic morphological changes. This is the first study reporting that c-Abl tyrosine kinase as a novel upstream activator of MST1 and BIM plays an important role in prion-induced neuron apoptosis via mitochondrial dysfunction. Our findings suggest that c-Abl tyrosine kinase is a potential therapeutic target for prion disease.

Keywords

Prion diseases c-Abl tyrosine kinase PrP106-126 Mitochondrial dysfunction Cell death 

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Bo Pan
    • 1
  • Lifeng Yang
    • 1
  • Jin Wang
    • 1
  • Yunsheng Wang
    • 1
  • Jihong Wang
    • 1
  • Xiangmei Zhou
    • 1
  • Xiaomin Yin
    • 1
  • Zhongqiu Zhang
    • 2
  • Deming Zhao
    • 1
  1. 1.State Key Lab of Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary MedicineChina Agricultural UniversityBeijingPeople’s Republic of China
  2. 2.Veterinary BureauMinistry of Agriculture of the People’s Republic of ChinaBeijingPeople’s Republic of China

Personalised recommendations