title: STI571 protects neuronal cells from neurotoxic prion protein fragment-induced apoptosis.
abstract: Prion diseases are neurodegenerative disorders caused by the accumulation of misfolded prion proteins [scrapie form of PrP (PrP(Sc))]. PrP(Sc) accumulation in the brain causes neurotoxicity by inducing mitochondrial-apoptotic pathways. Neurodegeneration can be prevented by imatinib mesylate (Gleevec or STI571) that regulates c-Abl tyrosine kinases, which elicit protective effects in neurodegenerative disease models. However, the protective effect of STI571 against prion disease remains unknown. In the present study, the effect of STI571 on prion peptide-induced neuronal death was investigated. Results showed that STI571 rescued neurons from PrP106-126-induced neurotoxicity by preventing mitochondrial dysfunction. STI571-inhibited c-Abl tyrosine kinases prevented PrP106-126-induced reduction in mitochondrial potential, Bax translocation to the mitochondria and cytochrome c release. The protective effect of STI571 against mitochondrial dysfunction was related to the activation of BIM expression. This study is the first to demonstrate the protective effect of STI571 against prion-mediated neurotoxicity. Our results suggested that imatinib mesylate treatment may be a novel therapeutic strategy to treat prion-mediated neurotoxicity.
authors: Department of Veterinary Pathology, College of Animal Sciences, Henan Institute of Science and Technology, Xinxiang, China. Electronic address: panyaoqian@163.com.
authors: Yaoqian
authors: Y
authors: Pan
authors: Department of Veterinary Pathology, College of Animal Sciences, Henan Institute of Science and Technology, Xinxiang, China; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45Chang-Chun Street, Xicheng District, Beijing 100053, China. Electronic address: 5439705@qq.com.
authors: Liyong
authors: L
authors: Sun
authors: Department of Veterinary Pathology, College of Animal Sciences, Henan Institute of Science and Technology, Xinxiang, China. Electronic address: Wangjihong2007@hotmail.com.
authors: Jihong
authors: J
authors: Wang
authors: Department of Veterinary Pathology, College of Animal Sciences, Henan Institute of Science and Technology, Xinxiang, China; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45Chang-Chun Street, Xicheng District, Beijing 100053, China. Electronic address: 172773911@qq.com.
authors: Wenzhuo
authors: W
authors: Fu
authors: Department of Veterinary Pathology, College of Animal Sciences, Henan Institute of Science and Technology, Xinxiang, China. Electronic address: fyyabu@126.com.
authors: Yongyao
authors: Y
authors: Fu
authors: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 20 Dong-Da Street, Fengtai District, Beijing 100071, China. Electronic address: wangjin6979@126.com.
authors: Jin
authors: J
authors: Wang
authors: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 20 Dong-Da Street, Fengtai District, Beijing 100071, China. Electronic address: tong.yigang@gmail.com.
authors: Yigang
authors: Y
authors: Tong
authors: Department of Veterinary Pathology, College of Animal Sciences, Henan Institute of Science and Technology, Xinxiang, China; State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 20 Dong-Da Street, Fengtai District, Beijing 100071, China. Electronic address: panbo198401@163.com.
authors: Bo
authors: B
authors: Pan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity*; D011328:Prions / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C099283:Laptm4a protein, mouse; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011328:Prions; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C082632:prion protein (106-126); D000068877:Imatinib Mesylate; D020169:Caspases
keywords: Imatinib mesylate; Neuronal death; PrP106-126; Prion diseases; c-Abl tyrosine kinase