c-Abl Tyrosine Kinase Mediates Neurotoxic Prion Peptide-Induced Neuronal Apoptosis via Regulating Mitochondrial Homeostasis
c-Abl Tyrosine Kinase Mediates Neurotoxic Prion Peptide-Induced Neuronal Apoptosis via Regulating Mitochondrial Homeostasis
复制标题
c-Abl 酪氨酸激酶通过调节线粒体稳态介导神经毒性朊病毒肽诱导的神经元凋亡
DOI：
10.1007/s12035-014-8646-4
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发表时间：
2014-04-01
影响因子：
5.1
通讯作者：
Zhao, Deming
中科院分区：
文献类型：
--
作者：
Pan, Bo;Yang, Lifeng;Zhao, Deming
朊病毒病是一种神经退行性疾病，其特征在于与疾病相关的朊病毒蛋白的积累和凋亡性神经元死亡。以往的研究表明，c-Abl酪氨酸激酶的普遍表达转导各种外在和内在的细胞信号。在这项研究中，我们证明，一个合成的神经毒性朊病毒片段（PrP 106 -126）激活c-Abl酪氨酸激酶，这反过来又引发了MST 1和BIM的上调，表明c-Abl-BIM信号通路的激活。在神经元培养物中，发现肽片段通过线粒体功能障碍导致细胞死亡。使用小干扰RNA敲低c-Abl保护神经元细胞免受PrP 106 -126诱导的线粒体功能障碍、活性氧物质的产生和诱导Bax易位至线粒体、细胞色素c释放至胞质溶胶以及半胱天冬酶-9和半胱天冬酶-3活化的凋亡事件。阻断c-Abl酪氨酸激酶也可防止PrP 106 -126诱导的神经细胞凋亡形态学变化。这是首次报道c-Abl酪氨酸激酶作为MST 1和BIM的一种新型上游激活剂，在朊病毒通过线粒体功能障碍诱导的神经元凋亡中发挥重要作用。我们的研究结果表明，c-Abl酪氨酸激酶是一个潜在的治疗靶点朊病毒疾病。
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.