title: C-Abl tyrosine kinase mediates neurotoxic prion peptide-induced neuronal apoptosis via regulating mitochondrial homeostasis.
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.
authors: 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, Beijing, 100193, People's Republic of China, panbo198401@163.com.
authors: Bo
authors: B
authors: Pan
authors: Lifeng
authors: L
authors: Yang
authors: Jin
authors: J
authors: Wang
authors: Yunsheng
authors: Y
authors: Wang
authors: Jihong
authors: J
authors: Wang
authors: Xiangmei
authors: X
authors: Zhou
authors: Xiaomin
authors: X
authors: Yin
authors: Zhongqiu
authors: Z
authors: Zhang
authors: Deming
authors: D
authors: Zhao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016313:Genes, abl / Q000187:drug effects / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000633:toxicity*; D011328:Prions / Q000633:toxicity*; D051381:Rats
chemical_list: D010446:Peptide Fragments; D011328:Prions; C082632:prion protein (106-126)