Critical role of neuronal pentraxin 1 in mitochondria-mediated hypoxic-ischemic neuronal injury.
Critical role of neuronal pentraxin 1 in mitochondria-mediated hypoxic-ischemic neuronal injury.
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DOI：
10.1016/j.nbd.2012.10.003
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发表时间：
2013-02
影响因子：
6.1
通讯作者：
Hossain MA
中科院分区：
文献类型：
--
作者：
Al Rahim M;Thatipamula S;Hossain MA
发育中的大脑对缺氧缺血性（HI）损伤非常敏感，导致存活的婴儿和儿童严重的神经功能障碍。以前，我们已经报道了诱导神经元pentraxin 1（NP 1），一种新的神经元蛋白的长正五聚蛋白家族，HI神经元损伤。在这里，我们研究了这种特定的信号是如何传播，导致HI神经元死亡。我们使用野生型（WT）和NP 1敲除（NP 1-KO）小鼠海马培养物，在暴露于氧葡萄糖剥夺（OGD）后体外建模，以及HI脑损伤的体内新生（P9-10）小鼠模型。我们的结果显示，与对侧相比，在OGD暴露（4-8h）后的原代海马神经元中以及在HI后24- 4 - 8h在同侧海马CA 1和CA 3区域中诱导NP 1。我们还发现PTEN活性增加与Akt（Ser 473）和GSK-3β（Ser 9）的OGD时间依赖性（4-8h）去磷酸化同时发生。OGD还引起Bad（Ser 136）和Bax蛋白水平磷酸化的时间依赖性降低。免疫荧光染色和亚细胞分级分析显示，增加线粒体易位的坏和Bax蛋白质从细胞质后OGD（4小时），同时增加释放的细胞色素C从线粒体，然后激活半胱天冬酶-3。NP 1蛋白与Bad和Bax蛋白发生免疫沉淀; OGD导致NP 1与Bad和Bax的相互作用增加，从而促进它们的线粒体易位和线粒体膜电位（Δ Vm）的耗散。在WT原代海马神经元中，这种NP 1诱导先于细胞色素C（Cyt C）释放到胞质溶胶中的线粒体增加、半胱天冬酶-3活化和OGD时间依赖性细胞死亡。相比之下，在NP 1-KO神经元中，没有Bad和Bax从细胞质易位到线粒体，并且没有证据表明Δ Δ Δ m丢失，增加了OGD后的Cyt C释放和caspase-3活化;这导致神经元死亡显著减少。我们的研究结果表明NP 1在Bad/Bad依赖的线粒体释放Cyt C和caspase-3激活中的调节作用。总之，我们的研究结果表明，NP 1调节海马驱动的海马细胞死亡的新机制，表明NP 1作为一个潜在的治疗靶点对新生儿HI脑损伤。
Developing brain is highly susceptible to hypoxic-ischemic (HI) injury leading to severe neurological disabilities in surviving infants and children. Previously, we have reported induction of neuronal pentraxin 1 (NP1), a novel neuronal protein of long-pentraxin family, following HI neuronal injury. Here, we investigated how this specific signal is propagated to cause the HI neuronal death. We used wild-type (WT) and NP1 knockout (NP1-KO) mouse hippocampal cultures, modeled in vitro following exposure to oxygen glucose deprivation (OGD), and in vivo neonatal (P9-10) mouse model of HI brain injury. Our results show induction of NP1 in primary hippocampal neurons following OGD exposure (4–8h) and in the ipsilateral hippocampal CA1 and CA3 regions at 24–48 h post-HI compared to the contralateral side. We also found increased PTEN activity concurrent with OGD time-dependent (4–8h) dephosphorylation of Akt (Ser473) and GSK-3β (Ser9). OGD also caused a time-dependent decrease in the phosphorylation of Bad (Ser136), and Bax protein levels. Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential (ΔΨm). This NP1 induction preceded the increased mitochondrial release of cytochrome C (Cyt C) into the cytosol, activation of caspase-3 and OGD time-dependent cell death in WT primary hippocampal neurons. In contrast, in NP1-KO neurons there was no translocation of Bad and Bax from cytosol to the mitochondria, and no evidence of ΔΨm loss, increased Cyt C release and caspase-3 activation following OGD; which resulted in significantly reduced neuronal death. Our results indicate a regulatory role of NP1 in Bad/Bax-dependent mitochondrial release of Cyt C and caspase-3 activation. Together our findings demonstrate a novel mechanism by which NP1 regulates mitochondria-driven hippocampal cell death; suggesting NP1 as a potential therapeutic target against HI brain injury in neonates.
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影响因子：
8.3
作者：
Gresham, GE;Alexander, D;Trombly, CA
通讯作者：
Trombly, CA
DOI：
10.1073/pnas.100121097
发表时间：
2000-05-23
影响因子：
11.1
作者：
Budd, SL;Tenneti, L;Lipton, SA
通讯作者：
Lipton, SA
影响因子：
5.9
作者：
Kalenderian, Elsbeth;Pegus, Cheryl;Lasa, Damaris
通讯作者：
Lasa, Damaris
影响因子：
1.7
作者：
Johnston, MV
通讯作者：
Johnston, MV
影响因子：
3.6
作者：
Enguita, M;DeGregorio-Rocasolano, N;Trullas, R
通讯作者：
Trullas, R