期刊
MOLECULAR NEUROBIOLOGY
卷 49, 期 2, 页码 1102-1116出版社
SPRINGER
DOI: 10.1007/s12035-014-8646-4
关键词
Priondiseases; c-Abltyrosinekinase; PrP106-126; Mitochondrial dysfunction; Cell death
资金
- Natural Science Foundation of China [31172293, 31001048, 31272532]
- Ministry of Agriculture Program of China [2013-S11]
- Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP) [20100008120002]
- Foundation of Chinese Ministry of Science and Technology [2011BAI15B01]
- Program for Cheung Kong Scholars and Innovative Research Team in University of China [IRT0866]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据