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

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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.

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Acknowledgments

The authors thank Prof. ** Zhu, Dr. Sher Hayat Khan, Dr. Yang Yang, Dr. Ting Zhu, and Dr. Fushan Shi for their valuable suggestions and critical reading of this manuscript. This work was supported by the Natural Science Foundation of China (project nos. 31172293, 31001048, and 31272532), the Ministry of Agriculture Program of China (no. 2013-S11), the Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP, project no. 20100008120002), the Foundation of Chinese Ministry of Science and Technology (project no. 2011BAI15B01), and the Program for Cheung Kong Scholars and Innovative Research Team in University of China (no. IRT0866).

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  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 Medicine, China Agricultural University, Bei**g, 100193, People’s Republic of China

    Bo Pan, Lifeng Yang, ** Wang, Yunsheng Wang, Jihong Wang, **angmei Zhou, **aomin Yin & Deming Zhao

  2. Veterinary Bureau, Ministry of Agriculture of the People’s Republic of China, Bei**g, People’s Republic of China

    Zhongqiu Zhang

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Correspondence to Deming Zhao.

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Bo Pan and Lifeng Yang contributed to this work equally.

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Pan, B., Yang, L., Wang, J. et al. c-Abl Tyrosine Kinase Mediates Neurotoxic Prion Peptide-Induced Neuronal Apoptosis via Regulating Mitochondrial Homeostasis. Mol Neurobiol 49, 1102–1116 (2014). https://doi.org/10.1007/s12035-014-8646-4

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