2004 Fiscal Year Final Research Report Summary
Clarification of the mechanism underlying y-secretase cleavage by presenilin complexes
| Project/Area Number |
13210067
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
NISHIMURA Masaki Shiga University of Medical Science Molecular, Neuroscience Research Center, Associate Professor, 分子神経科学研究センター, 助教授 (40322739)
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| Project Period (FY) |
2001 – 2004
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| Keywords | Alzheimer disease / Presenilin / Nicastrin / β-amyloid / γ-secretase |
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| Research Abstract |
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).
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Research Products
(26 results)
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[Journal Article] Random mutagenesis of presenilin 1 identifies novel mutants exclusively generating long amyloid β peptides.2005
Author(s)
Nakaya Y, Yamane T, Shiraishi H, Wang HQ, Matsubara E, Sato T, Dolios G, Wang R, De Strooper B, Shoji M, Komano H, Yanagisawa K, Ihara Y, Fraser P, St George-Hyslop P, Nishimura M.
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Journal Title
J Biol Chem 280(19)
Pages: 19070-19077
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2.2005
Author(s)
Wang HQ, Nakaya Y, Du Z, Yamane T, Shirane M, Kudo T, Takeda M, Takebayashi K, Noda Y, Nakayama KI, Nishimura M.
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Journal Title
Hum Mol Genet 14(13)
Pages: 1889-1902
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Coordinated metabolism of Alcadein and amyloid β-protein precursor regulates FE65-dependent gene transactivation.2004
Author(s)
Araki Y, Miyagi N, Kato N, Yoshida T, Wada S, Nishimura M, Komano H, Yamamoto T, De Strooper B, Yamamoto K, Suzuki T.
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Journal Title
J Biol Chem 279(23)
Pages: 24343-24354
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Normal brain development in PS1 hypomorphic mice with markedly reduced y-secretase cleavage of βAPP.2002
Author(s)
Rozmahel R, Huang J, Chen F, Liang Y, Nguyen V, Ikeda M, Levesque G, Yu G, Nishimura M, Mathews P, Schmidt SD, Mercken M, Bergeron C, Westaway D, St George-Hyslop P.
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Journal Title
Neurobiol Aging 23(2)
Pages: 187-194
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Nicastrin binds to membrane-tethered Notch.2001
Author(s)
Chen F, Yu G, Arawaka S, Nishimura M, Kawarai T, Yu H, Tandon A, Supala A, Song YQ, Rogaeva E, Milman P, Sato C, Yu C, Janus C, Lee J, Song L, Zhang L, Fraser PE, St George-Hyslop PH.
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Journal Title
Nature Cell Biol 3(8)
Pages: 751-754
Description
「研究成果報告書概要(欧文)」より
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