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-分泌酶活性所必需的。γ-分泌酶介导淀粉样前体蛋白（APP）的膜内切割，导致称为淀粉样β（Aβ）的致病肽的产生。由于Aβ_（42/3）在AD的发病机制中起着重要作用，因此阐明这一机制一直是AD研究的热点。我们已经揭示，早老素通过与nicastrin和其它蛋白质一起形成大分子复合物来介导APP和Notch的γ-分泌酶切割（Nat Cell Biol，2001），并且另一种组分PEN-2增强γ-分泌酶底物的可及性（J Neurochem，2004）。早老素中引起FAD的突变通过改变γ-分泌酶活性增加了较长Aβ_<42/43>的产生，但其潜在机制尚不清楚。利用早老素1（PS1）的随机突变筛选，我们鉴定了包括R278 I-PS1和L435 H-PS1在内的五种独特突变体，其仅产生高水平的Aβ_，<43>但不支持生理性PS1内蛋白水解或Aβ_<40>产生（J Biol Chem，2005）。细胞生物学研究和药理学研究表明，PS1突变和γ-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介导的。我们的研究结果表明，小分子可以被设计成诱导交替的PS复合物构象，这更有利于Aβ_<40>而不是致病性Aβ_&lt;42/43&gt;的产生。此外，我们报道早老素通过结合FKBP 38并减少线粒体中的抗凋亡Bcl-2而发挥促凋亡作用。此外，早老素的FAD突变增强了这种促凋亡活性，使神经元对脑中的凋亡刺激物敏感（AgNOMol Genet，出版中）。

项目成果

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.

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

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.

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

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