Research for requirement of down-regulation of energy metabolism for neuronal differentiation

神经元分化所需能量代谢下调的研究

• 批准号: 17500263
• 负责人: OHSAWA Ikuroh
• 金额: $ 2.35万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17500263/
• 关键词: Neuroscience; Differentiation; Mitochondria; Brain; Signal transduction

Only a few human neuroblastoma cell-lines maintain the potential for neuronal differentiation. We noticed by chance that differentiable human neuroblastomas including SH-SY5Y have a specific mutation in the dihydrolipoamide-succinyltransferase (DLST) gene, whose product is a component of the α-ketoglutarate-dehydrogenase complex involved in mitochondrial energy metabolism. Here we demonstrate a requirement of energy-reduction for neuronal differentiation by restoring SH-SY5Y with the wild-type DLSTgene. Up-regulation of DLST activity increased mitochondrial membrane potential and impaired neuronal differentiation. The impairment was partially rescued by treatment with inhibitors of energy metabolism. Additionally, down-regulation of DLST expression with small interfering RNA enhanced neuronal differentiation in rat pheochromocytoma PC12 and primary cultured neocortical cells. We further found that mitochondrial membrane potential among SH-SY5Y cells was heterogeneous and lower in neuroblastic type cells. It is thus concluded that the casual mutation conferred the potential for differentiation on the neuroblastomas, suggesting that such mutants had been preferentially selected as a model cell-line for neuronal differentiation. The energy-reduction seemed to contribute to the differentiation by preventing cell-death. These results provide a new insight into neuronal differentiation.

只有少数人神经母细胞瘤细胞系保持神经元分化的潜力。我们偶然注意到，包括SH-SY 5 Y在内的可分化的人类神经母细胞瘤在二氢硫辛酰胺-琥珀酰转移酶（DLST）基因中具有特异性突变，其产物是参与线粒体能量代谢的α-酮戊二酸脱氢酶复合物的组分。在这里，我们证明了一个需要的能量减少神经元分化恢复SH-SY 5 Y与野生型DLST基因。DLST活性的上调增加线粒体膜电位和受损的神经元分化。通过能量代谢抑制剂的治疗，损伤得到部分挽救。此外，用小干扰RNA下调DLST表达增强了大鼠嗜铬细胞瘤PC 12和原代培养的新皮质细胞的神经元分化。我们进一步发现，SH-SY 5 Y细胞的线粒体膜电位是不均匀的，在神经母细胞型细胞中较低。因此，可以得出结论，偶然突变赋予分化的神经母细胞瘤的潜力，这表明，这样的突变体已被优先选择作为神经元分化的模型细胞系。能量减少似乎通过防止细胞死亡而有助于分化。这些结果为神经元分化提供了新的见解。

项目成果

ミトコンドリアに局在するAβ結合アルコール脱水素酵素による酸化ストレスからの防御機構

线粒体中 Aβ 结合乙醇脱氢酶对抗氧化应激的防御机制

• 发表时间: 2008
• 期刊: アルツハイマー病-基礎研究から予防・治療の新しいパラダイム-日本臨牀 66(増刊)1
• 作者: Nobuaki EGASKIRA;Katsunori IWASAKI;Akihiko TAKASHIMA;Takuya WATANABE;Hideyuki KAWABE;Tomomi MATSUDA;Kenichi MISHIMA;Shozo CHIDORI;Ryoji NiSHIMURA;Michihiro FUJIWARA;KATURA KI.;Kogiku M.;大澤 郁朗;村上 弥生
• 通讯作者: 村上 弥生

新しい抗酸化治療法:細胞障害性酸素ラジカルの水素による選択的還元

一种新的抗氧化疗法：用氢选择性减少细胞毒性氧自由基

• 发表时间: 2007
• 作者: Sudo;K.;大澤 郁朗;大澤郁朗
• 通讯作者: 大澤郁朗

酸化ストレスに伴う老化関連疾患を示すトランスジェニック動物

转基因动物表现出与氧化应激相关的衰老相关疾病

• 发表时间: 2003

Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress

• DOI: 10.1016/j.bbrc.2007.07.088
• 发表时间: 2007-09-28
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Fukuda, Kei-Ichi;Asoh, Sadamitsu;Ohta, Shigeo
• 通讯作者: Ohta, Shigeo

Cytoprotective role of mitochondrial amyloid beta peptide-binding alcohol dehydrogenase against a cytotoxic aldehyde.

线粒体淀粉样β肽结合醇脱氢酶对细胞毒性醛的细胞保护作用。

• 发表时间: 2007
• 期刊: Neurobiol. Aging (In press)
• 作者: Ohsawa;I.;Ishikawa;M.;Takahashi;K.;Watanabe;M.;Nishimaki;K.;Yamagata;K.;Katsura;Katayama;Y.;Asoh;S.;Ohta;S;Murakami Y.
• 通讯作者: Murakami Y.