Establishment of therapeutic method for neurodegenerative diseases by specific protein degradation system for abnormal proteinsEstablishment of therapeutic method for neurodegenerative diseases by specific protein degradation system for abnormal proteins

异常蛋白特异性蛋白降解系统治疗神经退行性疾病方法的建立通过异常蛋白特异性蛋白降解系统治疗神经退行性疾病的方法

• 批准号: 13557057
• 负责人: HATAKEYAMA Shigetsugu
• 金额: $ 7.74万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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-13557057/
• 关键词: ubiquitin; Ubiquitin ligase; Neurodegenerative disease; MJD; Quality control; U-box protein; UFD2; VCP; SCF; NF-κB; カテニン; p27; Skp2; U-ボックス

Intracellular protein degradation is involved in the regulation of biologically important phenomenon including cell cycle, transcriptional regulation and signal transduction. Ubiquitylation is mediated by a multienzyme cascade and involves the formation by ubiquitin of thiol esters with at least two, and, in most instances, three, distinct types of enzyme: an E1, an E2, and an E3.Then Polyubiquitylated proteins are recognized and degraded by proteasomes. In this cascade, E3 enzymes are thought to determine the substrate specificity of ubiquitylation and have been classified into two families, the HECT and RING-finger families.The prototype U-box protein, yeast Ufd2, was identified as a ubiquitin-chain assembly factor (E4) that cooperates with a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein ligase (E3) to catalyze ubiquitin chain formation on artificial substrates. The U-box is a domain of -70 amino acids that is present in proteins from … More yeast to humans. We have reported that six mammalian U-box proteins have now been shown to mediate polyubiquitiylation in the presence of E1 and E2 and in the absence of E3. These data may suggest that U-box proteins constitute a third family of E3 enzymes. Almost U-box proteins interact with molecular chaperones, indicating that U-box type E3 is likely to be a chaperone-dependent E3. To deal with the accumulation of abnormal proteins, molecular chaperones refold abnormal proteins and U-box type E3 seems lo degrade misfolded proteins.Machado-Joseph disease (MJD) is caused by expansion of a polyglutamine tract in the protein MJD1 and this form of MJD1 proteins accumulates in neuron and cause neuronal dysfunction. We have reported that one of the mammalian U-box protein. UFD2a mediated polyubiquitylation of MJD1. We reported that other U-box protein CHIP also is related to Parkinson's disease. We are on going to establish the therapeutic method for neurodegenerative diseases with U-box type E3. Less

细胞内蛋白质降解参与细胞周期、转录调控和信号转导等重要生物学现象的调控。泛素化是由多酶级联反应介导的，涉及泛素与至少两种，在大多数情况下是三种不同类型的酶（E1、E2和E3）形成硫羟酸酯，然后多泛素化蛋白被蛋白酶体识别和降解。在这个级联反应中，E3酶被认为决定了泛素化的底物特异性，并已被分为两个家族，HECT和环指家族。原型U盒蛋白，酵母Ufd 2，被鉴定为泛素链组装因子（E4），与泛素激活酶（E1），泛素缀合酶（E2），和泛素-蛋白质连接酶（E3）以催化在人工底物上形成泛素链。U盒是存在于来自以下的蛋白质中的约70个氨基酸的结构域： ...更多信息 酵母对人类我们已经报道了六种哺乳动物的U盒蛋白质现在已经被证明在E1和E2的存在下以及在E3的不存在下介导多聚泛素化。这些数据可能表明，U-box蛋白构成了E3酶的第三个家族。几乎所有的U-box蛋白都与分子伴侣相互作用，表明U-box型E3很可能是一种依赖于分子伴侣的E3。Machado-Joseph病（Machado-Joseph disease，MJD）是由MJD 1蛋白中的多聚谷氨酰胺（polyglutaminamine，polyglutaminamine）片段扩增引起的，这种形式的MJD 1蛋白在神经元中积累，导致神经元功能障碍。我们已经报道了哺乳动物的一个U-box蛋白。UFD 2a介导的MJD 1的多泛素化。我们报道了其他的U-box蛋白CHIP也与帕金森病有关。我们将建立一个治疗神经退行性疾病的方法与U-box类型E3。少

项目成果

Ageta, H. et al.: "Regulation of the level of Vesl-1S/Homer-1a proteins by ubiquitin proteasome proteolytic system"J. Biol. Chem.. 276. 15893-15897 (2001)

Ageta, H. 等人：“泛素蛋白酶体蛋白水解系统对 Vesl-1S/Homer-1a 蛋白水平的调节”J.

Murillas, R et al.: "Identification of developmentally expressed proteins that functionally interact with Nedd4 ubiquitin ligase"J. Biol. Chem.. 277. 2897-2907 (2002)

Murillas, R 等人：“与 Nedd4 泛素连接酶功能性相互作用的发育表达蛋白的鉴定”J.

Miyamoto, A.: "Increased proliferation of B cells and autoimmune disease in protein kinase C-delta-deficient mice"Nature. 416. 865-869 (2002)

Miyamoto, A.：“蛋白激酶 C-δ 缺陷小鼠中 B 细胞增殖增加和自身免疫性疾病”《自然》杂志。

Kamizono, S. et al.: "Increased proliferation of B cells and autoimmune disease in protein kinase C-delta-deficient mice"J. Biol. Chem.. 276. 12530-12538 (2001)

Kamizono, S. 等人：“蛋白激酶 C-δ 缺陷小鼠中 B 细胞增殖增加和自身免疫性疾病”J.

Nakamichi, I.: "Formation of Mallory body-like inclusions and cell death induced by deregulated expression of keratin 18"Mol. Biol. Cell. 13. 3441-2451 (2002)

Nakamichi, I.：“角蛋白 18 表达失调诱导马洛里体样内含物的形成和细胞死亡”Mol。