The Role of stress proteins in the aggregation and cytotoxicity of polyglutamine

应激蛋白在聚谷氨酰胺聚集和细胞毒性中的作用

• 批准号: 13210155
• 负责人: KIMURA Yoko
• 金额: $ 19.2万
• 依托单位: Tokyo Metropolitan Organization for Medical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13210155/
• 关键词: polyglutamine; neurodegerative disease; molecular chaperone; amyloid; AAA superfamily protein; aggregates; Hsp104; VCP; p97; AAA+ スーパーファミリー蛋白質; 神経変性疾患; コンフォーメーション; 構造変換; コンフォーメーション病; 酵母

The polyglutamine diseases are caused by the expression of expanded unstable CAG repeats that code for polyglutamine in the responsible genes. These diseases are recognized as a type with a conformationally abnormal or amyloid-related proteins. We identified VCP/p97, one of AAA^+ superfamily proteins, that directly binds to polyglutamine in vitro, and that functions as an enhancer of neurodegeration by polyglutamine expressed in a fly model. We also found that vacuolar formation is one of hallmarks followed by cell death by the expression of polyglutamine in cultured cell systems. Hsp104, another member of AAA^+ superfamily proteins, is required for aggregate formation of polyglutamine expressed in yeast. As polyglutamine takes a form of amyoid in various systems, these results suggest a possibility that some molecular chaperones facilitate amyloid formation of polyglutamines. We further investigated how these molecular chaperones work on polyglutamine. We found that a certain amount of pre-existing polyglutamine aggregates are required for Hsp 104 to enhance the polyglutamine aggregation.

多聚谷氨酰胺疾病是由负责基因中编码多聚谷氨酰胺的扩增的不稳定CAG重复序列的表达引起的。这些疾病被认为是构象异常或淀粉样蛋白相关蛋白的类型。我们鉴定了VCP/p97，它是AAA^+超家族蛋白之一，在体外可直接与多聚谷氨酰胺结合，在果蝇模型中可作为多聚谷氨酰胺的神经变性增强剂发挥作用。我们还发现，空泡的形成是一个标志，其次是细胞死亡的多聚谷氨酰胺在培养的细胞系统中的表达。Hsp 104是AAA^+超家族蛋白的另一个成员，是酵母中表达的多聚谷氨酰胺聚集体形成所必需的。由于多聚谷氨酰胺在不同的系统中以淀粉样蛋白的形式存在，这些结果表明某些分子伴侣可能促进多聚谷氨酰胺的淀粉样蛋白形成。我们进一步研究了这些分子伴侣如何对聚谷氨酰胺起作用。我们发现，一定量的预先存在的多聚谷氨酰胺聚集体需要热休克蛋白104，以提高多聚谷氨酰胺聚集。

项目成果

木村 洋子: "ポリグルタミン病と分子シャペロン"神経研究の進歩. 46. 697-703 (2002)

Yoko Kimura：“多聚谷氨酰胺疾病和分子伴侣”神经学研究进展 46. 697-703 (2002)。

Circumvention of chaperone requirement for aggregate formation of a short polyglutamine tract by the co-expression of a long polyglutamine tract

通过长聚谷氨酰胺束的共表达来规避短聚谷氨酰胺束聚集体形成的伴侣要求

• 发表时间: 2002
• 期刊: J. Biol. Chem. 277
• 作者: Kimura Y.;et al.;Matsumoto et al.;Kimura Y. et al.
• 通讯作者: Kimura Y. et al.

Circumvention of chaperone requirement for aggregate formation of a short polyglutamine tract by the co-expression of a long polyglutamine tract.

通过长聚谷氨酰胺束的共表达来规避短聚谷氨酰胺束聚集体形成的伴侣要求。

• 发表时间: 2002
• 期刊: J.Biol.Chem. 277
• 作者: Kimura Y;et al.
• 通讯作者: et al.

Kimura Y, Koitabashi S, Kakizuka A, Fujita T.: "Circumvention of chaperone requirement for aggregate formation of a short polyglutamine tract by the co-expression of a long polyglutamine tract"J.Biol.Chem.. 277. 37536-37541 (2002)

Kimura Y、Koitabashi S、Kakizuka A、Fujita T.：“通过长聚谷氨酰胺束的共表达来规避短聚谷氨酰胺束聚集形成的伴侣要求”J.Biol.Chem.. 277. 37536-37541（

Higashiyama et. al: "Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegenerations in Drosophila"Cell Death and Differentiation. 9(3). 264-273 (2002)

东山等。