Defective cholesterol traffic and neuronal differentiation in neural stem cells of Niemann-Pick type C disease improved by valproic acid, a histone deacetylase inhibitor
Defective cholesterol traffic and neuronal differentiation in neural stem cells of Niemann-Pick type C disease improved by valproic acid, a histone deacetylase inhibitor
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DOI：
10.1016/j.bbrc.2007.06.116
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发表时间：
2007-08-31
影响因子：
3.1
通讯作者：
Kang, Kyung-Sun
中科院分区：
文献类型：
--
作者：
Kim, Sun-Jung;Lee, Bong-Hee;Kang, Kyung-Sun
C 型尼曼-匹克病 (NPC) 是一种神经退行性和脂质储存障碍，目前尚无有效的治疗方法。我们之前报道过，来自 NPC1 小鼠的神经干细胞表现出自我更新和分化受损。我们研究了历史悠久的脱乙酰酶抑制剂丙戊酸（VPA）是否可以增强神经元分化并恢复神经干细胞中缺陷的胆固醇代谢； (NSC) 来自 NPC1 缺陷小鼠 (NPC1(-/-))。 VPA 可以诱导神经元分化并恢复 NPC1(-/-) 小鼠 NSC 中受损的星形胶质细胞。重要的是，VPA 可以降低 NPC1(-/-) 小鼠 NSC 内胆固醇水平的升高。此外，VPA 处理抑制 REST/NRSF 和 HDAC 复合体，从而上调必需神经营养基因（Trk B、BDNF、MnSoD 和 NeuroD）。上调的神经营养基因能够增强 NPC1(-/-) 小鼠神经干细胞的神经分化和胆固醇稳态。在这项研究中，我们建议与胆固醇稳态一起。通过抑制 VPA 治疗诱导的 HDAC 和 REST/NRSF 活性，可以挽救神经元分化受损和星形胶质细胞形态异常。 (c) 2007 年，爱思唯尔公司出版。
Niemann-Pick type C disease (NPC) is a neurodegenerative and lipid storage disorder for which no effective treatment is known. We previously reported that neural stem cells derived from NPC1 mice showed impaired self-renewal and differentiation. We examined whether valproic acid (VPA), a historic deacetylase inhibitor, Could enhance neuronal differentiation and recover defective cholesterol metabolism in neural stem cell; (NSCs) from NPC1-deficient mice (NPC1(-/-)). VPA could induce neuronal differentiation and restore impaired astrocytes in NSCs from NPC1(-/-) mice. Importantly, an increasing level of cholesterol within NSCs from NPC1(-/-) mice could be reduced by VPA. Moreover, essential neurotrophic genes (Trk B, BDNF, MnSoD, and NeuroD) were up-regulated through the repression of the REST/NRSF and HDAC complex by the VPA treatment. Up-regulated neurotrophic genes were able to enhance neural differentiation and cholesterol homeostasis in neural stem cells from NPC1(-/-) mice. In this study, we suggested that, along with cholesterol homeostasis. impaired neuronal differentiation and abnormal morphology of astrocytes could be rescued by the inhibition of HDAC and REST/NRSF activity induced by VPA treatment. (c) 2007 Published by Elsevier Inc.