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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation
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Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation

机译：酪氨酸激酶神经生长因子受体通过Abeta介导的磷酸化作用从生存转为凋亡

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摘要

The present study shows that increased Abeta production in hip-pocampal neurons, due to a failure of NGF signal, induces an unexpected phosphorylation of tyrosine kinase receptor A (TrkA), followed by activation of the phospholipase C γ (PLCγ) pathway and neuronal death. Such phosphorylation seems causally connected with 2 kinases known be involved in amyloidogenesis, Src and CDK5, and associated with a and γ secretase-mediated p75 processing. Phar-macologic inhibition of TrkA phosphorylation and partial silencing of TrkA and/or p75 receptors prevent PLCy activation and protect neurons from death. Concomitantly with these events, TrkA, p75, Abeta peptides, and PS1 protein coimmunoprecipitate, suggesting their direct interplay in the subsequent onset of apoptotic death. Together, these findings depict a cellular mechanism whereby the same cellular transducing system may invert its intracellular message from trophic and antiapoptotic to a death signaling, which could also have relevance in the onset of Alzheimer's disease.
机译：本研究表明，由于NGF信号失败，海马神经元Abeta产量增加，导致酪氨酸激酶受体A（TrkA）意外磷酸化，随后激活磷脂酶Cγ（PLCγ）通路并导致神经元死亡。 。这种磷酸化似乎与已知参与淀粉样蛋白生成的2种激酶Src和CDK5因果相关，并且与α和γ分泌酶介导的p75加工有关。 TrkA磷酸化的药物生物学抑制和TrkA和/或p75受体的部分沉默可防止PLCy激活并保护神经元免于死亡。与这些事件同时发生的是，TrkA，p75，Abeta肽和PS1蛋白共免疫沉淀，表明它们在随后的凋亡死亡发作中直接相互作用。总之，这些发现描绘了一种细胞机制，通过该机制，同一细胞转导系统可以将其细胞内信息从营养和抗凋亡转变为死亡信号，这也可能与阿尔茨海默氏病的发作有关。

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  • 作者

    C. Matrone; R. Marolda; S. Ciafre; M. T. Ciotti; D. Mercanti; P. Calissano;

  • 作者单位

    Institute of Neurobiology and Molecular Medicine, National Research Council, via del Fosso del Fiorano 64, 00143 Rome, Italy;

    Institute of Neurobiology and Molecular Medicine, National Research Council, via del Fosso del Fiorano 64, 00143 Rome, Italy;

    Institute of Neurobiology and Molecular Medicine, National Research Council, via del Fosso del Fiorano 64, 00143 Rome, Italy;

    Institute of Neurobiology and Molecular Medicine, National Research Council, via del Fosso del Fiorano 64, 00143 Rome, Italy;

    Institute of Neurobiology and Molecular Medicine, National Research Council, via del Fosso del Fiorano 64, 00143 Rome, Italy;

    Institute of Neurobiology and Molecular Medicine, National Research Council, via del Fosso del Fiorano 64, 00143 Rome, Italy European Brain Research Institute, via del Fosso del Fiorano 64, 00143 Rome, Italy;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    Alzheimer's disease; neurodegeneration; neurotrophin; NGF; NGF receptors;

    机译：阿尔茨海默氏病;神经变性神经营养蛋白NGF;NGF受体;

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