Pre-B-cell colony-enhancing factor exerts a neuronal protection through its enzymatic activity and the reduction of mitochondrial dysfunction in in vitro ischemic models.
Pre-B-cell colony-enhancing factor exerts a neuronal protection through its enzymatic activity and the reduction of mitochondrial dysfunction in in vitro ischemic models.
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DOI：
10.1111/j.1471-4159.2011.07566.x
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发表时间：
2012-01
影响因子：
4.7
通讯作者：
Ding S
中科院分区：
文献类型：
--
作者：
Bi J;Li H;Ye SQ;Ding S
前B细胞集落增强因子（PBEF）是哺乳动物NAD+生物合成补救途径中将烟酰胺（NAM）转化为NMN的限速酶。以前我们发现PBEF仅在小鼠脑中的神经元中表达;在光血栓诱导的缺血中，杂合PBEF敲除（Pbef+/−）小鼠比野生型小鼠具有更大的缺血性病变。为了探讨PBEF对神经元保护作用的机制，本研究采用原代培养神经元的体外缺糖缺氧（OGD）和谷氨酸兴奋毒性模型。我们的研究结果表明，NAM和NAD+，底物和下游产品的PBEF，分别处理的神经元，显着减少神经元死亡后OGD和谷氨酸兴奋毒性，而FK 866，PBEF抑制剂处理的神经元，增加神经元死亡后OGD。此外，人PBEF（hPBEF）的过表达降低了谷氨酸兴奋毒性，而hPBEF突变体（即，H247 A和H247 E）对神经元死亡没有影响。我们进一步测试了PBEF对线粒体功能和生物发生的影响。我们的研究结果表明，NAD+和NAM的加入增加了OGD后神经元线粒体生物合成。在神经元中过表达PBEF降低谷氨酸刺激后的线粒体膜电位（MMP）去极化，而过表达H247 A和H247 E不影响MMP去极化。我们得出结论，PBEF通过其NAD+产生的酶活性，可以改善线粒体功能障碍，在缺血中具有神经保护作用。
Pre-B-Cell Colony-Enhancing Factor (PBEF) is known as a rate-limiting enzyme that converts nicotinamide (NAM) to NMN in the salvage pathway of mammalian NAD+ biosynthesis. Previously we found PBEF is exclusively expressed in neurons in the mouse brain; heterozygous PBEF knockout (Pbef+/−) mice have larger ischemic lesion than wild type mice in photothrombosis-induced ischemia. For the mechanistic study of neuronal protective role of PBEF, we used in vitro oxygen-glucose deprivation (OGD) and glutamate excitotoxicity models of primary cultured neurons in current study. Our results showed that the treatments of neurons with NAM and NAD+, the substrate and downstream product of PBEF, respectively, significantly reduced neuronal death after OGD and glutamate excitotoxicity, while treatment of neurons treated with FK866, a PBEF inhibitor, increased neuronal death after OGD. Furthermore, overexpression of human PBEF (hPBEF) reduced glutamate excitotoxicity, while overexpression of hPBEF mutants (i.e., H247A, and H247E) without enzymatic activity had no effect on neuronal death. We further tested the effect of PBEF on mitocondrial function and biogenesis. Our results show that addition of NAD+ and NAM increased mitochondrial biogenesis in neurons after OGD. Overexpression of PBEF in neurons reduced mitochondrial membrane potential (MMP) depolarization following glutamate stimulation, while overexpression of H247A and H247E did not affect MMP depolarization. We conclude that PBEF has a neuroprotective effect in ischemia through its enzymatic activity for NAD+ production that can ameliorate mitochondrial dysfunction.
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影响因子：
4.8
作者：
Balan, Vitaly;Miller, Gregory S.;Tzivion, Guri
通讯作者：
Tzivion, Guri
影响因子：
3.9
作者：
La Piana, G;Marzulli, D;Lofrumento, NE
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影响因子：
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作者：
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通讯作者：
Swanson, Raymond A.
影响因子：
20.1
作者：
Hsu CP;Oka S;Shao D;Hariharan N;Sadoshima J
通讯作者：
Sadoshima J
影响因子：
4.8
作者：
Bitterman, KJ;Anderson, RM;Sinclair, DA
通讯作者：
Sinclair, DA