Activation of the JNK-c-Jun pathway during the early phase of neuronal apoptosis induced by PrP106-126 and prion infection
Activation of the JNK-c-Jun pathway during the early phase of neuronal apoptosis induced by PrP106-126 and prion infection
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DOI：
10.1111/j.1460-9568.2005.04080.x
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发表时间：
2005-05-01
影响因子：
3.4
通讯作者：
Miquel, MC
中科院分区：
文献类型：
--
作者：
Carimalo, J;Cronier, S;Miquel, MC
朊病毒病是以神经元凋亡为特征的神经退行性疾病。虽然神经元凋亡的晚期执行阶段开始被表征，但在早期决策阶段发生的事件的顺序还不为人所知。在原代培养的鼠皮层神经元中，首先通过暴露于与人朊病毒蛋白（PrP）的残基106-126同源的合成肽PrP 106 - 126诱导细胞凋亡。暴露于其聚集形式在24小时内诱导大量神经元死亡。细胞凋亡的特点是核碎裂，神经炎性回缩和断裂和激活的caspase-3。在早期决策阶段，在3 h后检测到活性氧。使用免疫细胞化学，我们显示8小时后磷酸化c-Jun-N-末端激酶（JNK）易位进入细胞核的峰值，沿着细胞核c-Jun转录因子的激活。SP 600125对JNK的药理学抑制和c-Jun显性负性形式的过表达均显著降低神经元死亡，而MAPK p38抑制剂SB 203580则无影响。在原代培养的tg 338皮质神经元暴露于羊瘙痒病因子后，也研究了细胞凋亡。在该模型中，朊病毒诱导的神经元凋亡随时间逐渐增加，并在暴露2周后诱导40%的细胞死亡。免疫细胞化学分析显示7天后早期c-Jun活化。总之，JNK-c-Jun通路在PrP 106 -126诱导的神经元凋亡中起重要作用。该通路在羊瘙痒病感染期间也被激活，并且可能参与朊病毒诱导的神经元死亡。早期途径的药理学阻断为瘙痒症PrP为基础的病理开辟了新的治疗前景。
Prion diseases are neurodegenerative pathologies characterized by apoptotic neuronal death. Although the late execution phase of neuronal apoptosis is beginning to be characterized, the sequence of events occurring during the early decision phase is not yet well known. In murine cortical neurons in primary culture, apoptosis was first induced by exposure to a synthetic peptide homologous to residues 106-126 of the human prion protein (PrP), PrP106-126. Exposure to its aggregated form induced a massive neuronal death within 24 h. Apoptosis was characterized by nuclear fragmentation, neuritic retraction and fragmentation and activation of caspase-3. During the early decision phase, reactive oxygen species were detected after 3 h. Using immunocytochemistry, we showed a peak of phosphorylated c-Jun-N-terminal kinase (JNK) translocation into the nucleus after 8 h, along with the activation of the nuclear c-Jun transcription factor. Both pharmacological inhibition of JNK by SP600125 and overexpression of a dominant negative form of c-Jun significantly reduced neuronal death, while the MAPK p38 inhibitor SB203580 had no effect. Apoptosis was also studied after exposure of tg338 cortical neurons in primary culture to sheep scrapie agent. In this model, prion-induced neuronal apoptosis gradually increased with time and induced a 40% cell death after 2 weeks exposure . Immunocytochemical analysis showed early c-Jun activation after 7 days. In summary, the JNK-c-Jun pathway plays an important role in neuronal apoptosis induced by PrP106-126. This pathway is also activated during scrapie infection and may be involved in prion-induced neuronal death. Pharmacological blockade of early pathways opens new therapeutic prospects for scrapie PrP-based pathologies.