The catalytic core of γ-secretase:: Presenilin revisited

被引:33
作者
Steiner, Harald [1 ]
机构
[1] Univ Munich, Lab Neurodegenerat Dis Res, Dept Biochem, Adolf Butenandt Inst, D-80336 Munich, Germany
关键词
Alzheimer's disease; Amyloid beta-peptide; presenilin; gamma-secretase;
D O I
10.2174/156720508783954677
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Mutations in the presenilin 1 (PS1) gene are the major cause of familial Alzheimer's disease (AD). They effect an increased production of the highly neurotoxic 42 amino acid variant of the amyloid-beta peptide (A beta) which is believed to initiate the disease. A beta is the product of two consecutive cleavages of the beta-amyloid precursor protein (APP) by two proteases, beta-secretase and gamma-secretase. The latter enzyme has been identified as an intramembrane-cleaving multiprotein complex that apart from APP cleaves a large number of other type I transmembrane proteins. PS1 and its homologue PS2 are essential for gamma-secretase cleavage and more than a decade after their discovery it is now firmly established that they function as catalytic subunits of gamma-secretase. This review recapitulates the findings that led to this conclusion as well as the further progress made on the function of PS as gamma-secretase since then.
引用
收藏
页码:147 / 157
页数:11
相关论文
共 167 条
[81]   Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1 [J].
Li, YM ;
Xu, M ;
Lai, MT ;
Huang, Q ;
Castro, JL ;
DiMuzio-Mower, J ;
Harrison, T ;
Lellis, C ;
Nadin, JL ;
Neduvelil, JG ;
Register, RB ;
Sardana, MK ;
Shearman, MS ;
Smith, AL ;
Shi, XP ;
Yin, KC ;
Shafer, JA ;
Gardell, SJ .
NATURE, 2000, 405 (6787) :689-694
[82]   Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation [J].
Luo, Y ;
Bolon, B ;
Kahn, S ;
Bennett, BD ;
Babu-Khan, S ;
Denis, P ;
Fan, W ;
Kha, H ;
Zhang, JH ;
Gong, YH ;
Martin, L ;
Louis, JC ;
Yan, Q ;
Richards, WG ;
Citron, M ;
Vassar, R .
NATURE NEUROSCIENCE, 2001, 4 (03) :231-232
[83]   APH-1a is the principal mammalian APH-1 isoform present in γ-secretase complexes during embryonic development [J].
Ma, GJ ;
Li, T ;
Price, DL ;
Wong, PC .
JOURNAL OF NEUROSCIENCE, 2005, 25 (01) :192-198
[84]   Dissociated phenotypes in presenilin transgenic mice define functionally distinct γ-secretases [J].
Mastrangelo, P ;
Mathews, PM ;
Chishti, MA ;
Schmidtt, SD ;
Gu, YJ ;
Yang, J ;
Mazzella, MJ ;
Coomaraswamy, J ;
Horne, P ;
Strome, B ;
Pelly, H ;
Levesque, G ;
Ebeling, C ;
Jiang, Y ;
Nixon, RA ;
Rozmahel, R ;
Fraser, PE ;
St George-Hyslop, P ;
Carlson, GA ;
Westaway, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (25) :8972-8977
[85]   Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ42 production [J].
Moehlmann, T ;
Winkler, E ;
Xia, XF ;
Edbauer, D ;
Murrelll, J ;
Capell, A ;
Kaether, C ;
Zheng, H ;
Ghetti, B ;
Haass, C ;
Steiner, H .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (12) :8025-8030
[86]   Absence of endoproteolysis but no effects on amyloid β production by alternative splicing forms of presenilin-1, which lack exon 8 and replace D257A [J].
Morihara, T ;
Katayama, T ;
Sato, N ;
Yoneda, T ;
Manabe, T ;
Hitomi, J ;
Abe, H ;
Imaizumi, K ;
Tohyama, M .
MOLECULAR BRAIN RESEARCH, 2000, 85 (1-2) :85-90
[87]   A ligand-induced extracellular cleavage regulates γ-secretase-like proteolytic activation of Notch1 [J].
Mumm, JS ;
Schroeter, EH ;
Saxena, MT ;
Griesemer, A ;
Tian, XL ;
Pan, DJ ;
Ray, WJ ;
Kopan, R .
MOLECULAR CELL, 2000, 5 (02) :197-206
[88]   GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42 [J].
Munter, Lisa-Marie ;
Voigt, Philipp ;
Harmeier, Anja ;
Kaden, Daniela ;
Gottschalk, Kay E. ;
Weise, Christoph ;
Pipkorn, Ruediger ;
Schaefer, Michael ;
Langosch, Dieter ;
Multhaup, Gerd .
EMBO JOURNAL, 2007, 26 (06) :1702-1712
[89]   γ-Secretase, evidence for multiple proteolytic activities and influence of membrane positioning of substrate on generation of amyloid β peptides of varying length [J].
Murphy, MP ;
Hickman, LJ ;
Eckman, CB ;
Uljon, SN ;
Wang, R ;
Golde, TE .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (17) :11914-11923
[90]   Random mutagenesis of presenilin-1 identifies novel mutants exclusively generating long amyloid β-peptides [J].
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 .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (19) :19070-19077