Clarification of the mechanism underlying y-secretase cleavage by presenilin complexes

阐明早老素复合物裂解 y-分泌酶的机制

• 批准号: 13210067
• 负责人: NISHIMURA Masaki
• 金额: $ 31.68万
• 依托单位: Shiga University of Medical Science
• 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 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13210067/
• 关键词: Alzheimer disease; Presenilin; Nicastrin; β-amyloid; γ-secretase; γセクレターゼ

Presenilins, causative molecules for familial Alzheimer's disease (FAD), are required for y-secretase activity. y- Secretase mediates intramembrane cleavage of amyloid precursor protein (APP), resulting in generation of pathogenic peptides named amyloid β(Aβ). The clarification of this mechanism is a central issue in AD research, because the longer Aβ ending at residue 42 or 43 (Aβ_<42/3>) are thought to play a critical role in the pathogenesis of AD. We have revealed that presenilins mediate y-secretase cleavage of APP and Notch by forming macromolecular complexes together with nicastrin and other proteins (Nat Cell Biol, 2001), and that another component PEN-2 enhances the accessibility of the y-secretase substrates (J Neurochem, 2004). FAD- causing mutations in the presenilins increase production of longer Aβ_<42/43> by altering y-secretase activity, although the underlying mechanism remains unknown. Using a random mutagenesis screen of presenilin 1 (PS1), we identified five unique mutants including R278I-PS1 and L435H-PS1, which exclusively generated a high level of Aβ_<43> but that did not support physiological PS1 endoproteolysis or Aβ_<40> generation (J Biol Chem, 2005). Cell biological investigation and pharmacological study using the inhibitors suggest that the effects of PS1 mutations and y-secretase inhibitors on the specificity are commonly mediated through a conformational change in the complex. Our results suggest that small molecules could be designed to induce alternate PS complex conformations that are more favourable to the generation of Aβ_<40> rather than pathogenic Aβ_<42/43>. Additionally, we reported that presenilins exert a pro-apoptotic effect by binding to FKBP38 and reducing anti- apoptotic Bcl-2 in the mitochondria. Furthermore, FAD mutations of presenilins enhance this pro-apoptotic activity, sensitizing neurons to apoptotic stimuli in brains (Hum Mol Genet, in press).

早老素是家族性阿尔茨海默病 (FAD) 的致病分子，是 γ 分泌酶介导淀粉样前体蛋白 (APP) 膜内裂解所必需的，从而产生名为 β 淀粉样蛋白 (Aβ) 的致病肽。这种机制是 AD 研究的核心问题，因为较长的 Aβ 终止于残基 42 或 43 (Aβ_<42/3>)被认为在 AD 的发病机制中发挥着关键作用。我们已经揭示，早老素通过与尼卡斯特林和其他蛋白质形成大分子复合物来介导 APP 和 Notch 的 γ-分泌酶裂解（Nat Cell Biol，2001），而另一种成分 PEN 则被认为在 AD 的发病机制中发挥着关键作用。 -2 增强了 y-分泌酶底物的可及性（J Neurochem，2004），导致早老素中的 FAD 突变增加了较长的产生。 Aβ_<42/43> 通过改变 y-分泌酶活性，尽管潜在机制仍不清楚，但使用早老素 1 (PS1) 的随机诱变筛选，我们鉴定了五个独特的突变体，包括 R278I-PS1 和 L435H-PS1，它们专门产生了 Aβ_<42/43>。高水平的 Aβ_<43>，但不支持生理性 PS1 内切蛋白水解或 Aβ_<40> 生成（J Biol Chem， 2005）。使用抑制剂的细胞生物学研究和药理学研究表明，PS1 突变和 y-分泌酶抑制剂对特异性的影响通常是通过复合物的构象变化来介导的。我们的结果表明，可以设计小分子来诱导替代。 PS复合物构象更有利于Aβ_<40>而不是致病性Aβ_<42/43>的产生。此外，我们报道早老素通过结合发挥促凋亡作用。此外，早老素的 FAD 突变增强了这种促凋亡活性，使神经元对大脑中的凋亡刺激敏感（Hum Mol Genet，出版中）。

项目成果

Alzheimer病:Aβの生成抑制による治療戦略

阿尔茨海默病：通过抑制 Aβ 产生的治疗策略

• 发表时间: 2004
• 期刊: 最新医学 59・7
• 作者: Shiraishi H;et al.;西村正樹
• 通讯作者: 西村正樹

β-and γ-secretases as therapeutic targets for Alzheimer's disease.

β-和γ-分泌酶作为阿尔茨海默病的治疗靶点。

• 发表时间: 2004
• 期刊: Igaku no Ayumi 208(5)
• 作者: Wang HQ;Nakaya Y;Du Z;Yamane T;Shirane M;Kudo T;Takeda M;Takebayashi K;Noda Y;Nakayama KI;Nishimura M.;西村正樹;西村正樹;Yoichi Araki;Hirohisa Shiraishi;西村正樹;Nishimura M.
• 通讯作者: Nishimura M.

Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2

• DOI: 10.1093/hmg/ddi195
• 发表时间: 2005-07-01
• 期刊: HUMAN MOLECULAR GENETICS
• 影响因子: 3.5
• 作者: Wang, HQ;Nakaya, Y;Nishimura, M
• 通讯作者: Nishimura, M

Follistatin-related gene (FLRG) expression in human endometrium : sex steroid hormones regulate the expression of FLRG in cultured human endometrial stromal cells.

人子宫内膜中卵泡抑素相关基因（FLRG）的表达：性类固醇激素调节培养的人子宫内膜基质细胞中 FLRG 的表达。

• 发表时间: 2003
• 期刊: J Clin Endocrinol Metab 88・9
• 作者: Shiraishi H;et al.;西村正樹;Hua-Qin Wang
• 通讯作者: Hua-Qin Wang

Therapeutric strategy for Alzheimer disease : Inhibition of Amyloid β generation.

阿尔茨海默病的治疗策略：抑制β淀粉样蛋白的生成。

• 发表时间: 2004
• 期刊: Saishin Igaku 59(7)
• 作者: Shiraishi H;Sai X;Wang HQ;Maeda Y;Kurono Y;Nishimura M;Yanagisawa K;Komano H.;Nishimura M.
• 通讯作者: Nishimura M.