Transcriptional disturbance and Neurodegeneration.

转录紊乱和神经变性。

• 批准号: 15390272
• 负责人: ONODERA Osamu
• 金额: $ 9.54万
• 依托单位: NIIGATA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390272/
• 关键词: polyglutamine; spinocerebellar ataxia; CREB mediated transcription; UPS; APTX; DNA repair; XRCC1; poly(ADP-ribose)polymerase

By using isogenic stable inducible cell lines, we showed the polyglutamine stretch suppressed the CRE dependent transcription in their early stage. However their repressive effects were not so dramatically different in different cell lines which have different length of polyglutamine stretch. Furthermore its repressive effect is not affected the existence of aggregate formation. Taken together CRE mediated transcriptional repression was not a pathogenic for polyglutamine disease. By using these cell lines, we showed the expanded polyglutamine stretch retained in cell, speciously in nucleus by length dependent manner. The UPS, one of the main systems to degradate unfolded proteins in cells, was not suppressed in these cell lines. Therefore we speculated that polyglutamine stretch itself has resistance to degradation, thus accumulate in nucleus.The other neurodegenerative disorders, early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH/AOA1) is caused by mutation of APTX. We show the APTX binds to X-ray repair cross-complementing group 1 protein, which is the scaffold protein for base excision repair (BER) machinery in single strand DNA break repair (SSBR), and made complex with poly (ADP-ribose) polymerase. These findings support the idea that APTX might take an important role in SSBR system.

通过使用等基因稳定诱导细胞系，我们发现聚谷氨酰胺拉伸在早期阶段抑制了 CRE 依赖性转录。然而，在具有不同聚谷氨酰胺拉伸长度的不同细胞系中，它们的抑制作用并没有那么显着不同。此外，其抑制作用不影响聚集体形成的存在。总的来说，CRE 介导的转录抑制并不是多聚谷氨酰胺疾病的致病因素。通过使用这些细胞系，我们显示了扩展的聚谷氨酰胺延伸保留在细胞中，特别是通过长度依赖的方式保留在细胞核中。 UPS 是降解细胞中未折叠蛋白的主要系统之一，在这些细胞系中并未受到抑制。因此我们推测聚谷氨酰胺伸展本身具有抗降解性，从而在细胞核中积累。其他神经退行性疾病，早发性共济失调伴眼部运动失用和低白蛋白血症（EAOH/AOA1）是由APTX突变引起的。我们展示了 APTX 与 X 射线修复交叉互补组 1 蛋白结合，该蛋白是单链 DNA 断裂修复 (SSBR) 中碱基切除修复 (BER) 机制的支架蛋白，并与聚 (ADP-核糖) 聚合酶形成复合物。这些发现支持 APTX 可能在 SSBR 系统中发挥重要作用的观点。

项目成果

Severe generalized dystonia as a pressentation of a patient with aprataxin genemutation.

严重全身性肌张力障碍是 aprataxin 基因突变患者的表现。

• 发表时间: 2003
• 期刊: Mov Disord. 18(10)
• 作者: Sekijima Y;Hashimoto T;Onodera O;Date H;Okano T;Naito K;Tsuji S;Ikeda S.;Yamada E;Sekijima Y
• 通讯作者: Sekijima Y

小野寺理: "ポリグルタミン病の新展開"内科. 91巻6号. 1325 (2003)

Osamu Onodera：“多聚谷氨酰胺疾病的新进展”，第 91 卷，第 6. 1325 期（2003 年）。

Disruption of the toxic conformation of the expanded polyglutamine stretch leads to suppression of aggregate formation and cytotoxicity

扩展的聚谷氨酰胺延伸段的毒性构象的破坏导致聚集体形成和细胞毒性的抑制

• 发表时间: 2004
• 期刊: Biochem Biophys Res Commun 317・4
• 作者: Minatoguchi S;et al.;N.Fujikake;H.A.Popiel
• 通讯作者: H.A.Popiel

Aparataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein.

Aparataxin 是 EAOH 的致病蛋白，是一种核蛋白，具有作为 DNA 修复蛋白的潜在作用。

• 发表时间: 2004
• 期刊: Ann Neurol. 55(2)
• 作者: Terauchi;Y.;et al.;Feng J;Sano Y
• 通讯作者: Sano Y

Sano Y et al.: "Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein with a potential role as a DNA repair protein"Ann Neurol.. Feb;55(2). 241-249 (2004)

Sano Y 等人：“Aprataxin，EAOH 的致病蛋白，是一种核蛋白，具有作为 DNA 修复蛋白的潜在作用”Ann Neurol.. Feb；55(2)。