Striatal neurodevelopment is dysregulated in purine metabolism deficiency and impacts DARPP-32, BDNF/TrkB expression and signaling: new insights on the molecular and cellular basis of Lesch-Nyhan Syndrome.
Striatal neurodevelopment is dysregulated in purine metabolism deficiency and impacts DARPP-32, BDNF/TrkB expression and signaling: new insights on the molecular and cellular basis of Lesch-Nyhan Syndrome.
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DOI：
10.1371/journal.pone.0096575
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Pandori W
中科院分区：
文献类型：
--
作者：
Guibinga GH;Barron N;Pandori W
Lesch-Nyhan综合征（LNS）是由编码嘌呤代谢酶次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HPRT）的基因突变引起的神经发育障碍。这种综合征的特征是一系列严重的神经功能障碍，部分源于纹状体功能障碍。然而，这些功能障碍背后的分子和细胞机制仍然在很大程度上未被确定。在这份报告中，我们证明，HPRT缺陷导致纹状体图案，最值得注意的是纹状体富集的转录因子B细胞白血病11b（Bcl 11b）的关键基因的表达失调。数据还显示，下调表达的Bcl 11 b在HPRT缺陷永生化小鼠纹状体（STHdh）神经干细胞伴随着异常表达的一些转录伴侣和其他纹状体富集基因，包括基因编码多巴胺和cAMP调节磷蛋白32（DARPP-32）。此外，我们证明，BDNF/TrkB信号，DARPP-32纹状体表达的已知激活剂和Bcl 11b转录激活效应的组件显着增加HPRT缺陷细胞和HPRT敲除小鼠的纹状体。因此，HPRT缺陷细胞在暴露于过氧化氢时显示出对活性氧（ROS）介导的细胞死亡的上级保护。这些研究结果表明，HPRT缺乏引起的嘌呤代谢缺陷虽然可能对纹状体神经元提供神经保护，但会影响可能构成LNS神经发病机制的关键基因和信号通路。
Lesch-Nyhan Syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). This syndrome is characterized by an array of severe neurological impairments that in part originate from striatal dysfunctions. However, the molecular and cellular mechanisms underlying these dysfunctions remain largely unidentified. In this report, we demonstrate that HPRT-deficiency causes dysregulated expression of key genes essential for striatal patterning, most notably the striatally-enriched transcription factor B-cell leukemia 11b (Bcl11b). The data also reveal that the down-regulated expression of Bcl11b in HPRT-deficient immortalized mouse striatal (STHdh) neural stem cells is accompanied by aberrant expression of some of its transcriptional partners and other striatally-enriched genes, including the gene encoding dopamine- and cAMP-regulated phosphoprotein 32, (DARPP-32). Furthermore, we demonstrate that components of the BDNF/TrkB signaling, a known activator of DARPP-32 striatal expression and effector of Bcl11b transcriptional activation are markedly increased in HPRT-deficient cells and in the striatum of HPRT knockout mouse. Consequently, the HPRT-deficient cells display superior protection against reactive oxygen species (ROS)-mediated cell death upon exposure to hydrogen peroxide. These findings suggest that the purine metabolic defect caused by HPRT-deficiency, while it may provide neuroprotection to striatal neurons, affects key genes and signaling pathways that may underlie the neuropathogenesis of LNS.
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影响因子：
3.5
作者：
Guibinga, Ghiabe-Henri;Murray, Fiona;Hrustanovic, Gorjan
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