A loss of function mutant of the presenilin homologue SEL-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increases Aβ42 generation in human cells

被引:34
作者
Okochi, M
Eimer, S
Böttcher, A
Baumeister, R
Romig, H
Walter, J
Capell, A
Steiner, H
Haass, C
机构
[1] Univ Munich, Genzentrum, D-81377 Munich, Germany
[2] Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers Dis Res, D-80336 Munich, Germany
[3] Boehringer Ingelheim KG, CNS Res, D-55216 Ingelheim, Germany
关键词
D O I
10.1074/jbc.M005254200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The familial Alzheimer's disease-associated presenilins (PSs) occur as a dimeric complex of proteolytically generated fragments, which functionally supports endoproteolysis of Notch and the beta -amyloid precursor protein (beta APP). A homologous gene, sel-12, has been identified in Caenorhabditis elegans, We now demonstrate that wild-type (wt) SEL-12 undergoes endoproteolytic cleavage in C. elegans similar to the PSs in human tissue. In contrast, SEL-12 C60S protein expressed from the sel-12(ar131) allele is miscleaved in C. elegans, resulting in a larger mutant N-terminal fragment. Neither SEL-12 wt nor C60S undergo endoproteolytic processing upon expression in human cells, suggesting that SEL-12 is cleaved by a C, elegans-specific endoproteolytic activity. The loss of function of sel-12 in C. elegans is not associated with a dominant negative activity in human cells, because SEL-12 C60S and the corresponding PS1 C92S mutation do not interfere with Notch1 cleavage. Moreover, both mutant variants increase the aberrant production of the highly amyloidogenic 42-amino acid version of amyloid beta -peptide similar to familial Alzheimer's disease-associated human PS mutants. Our data therefore demonstrate that the C60S mutation in SEL-12 is associated with aberrant endoproteolysis and a loss of function in C, elegans, whereas a gain of misfunction is observed upon expression in human cells.
引用
收藏
页码:40925 / 40932
页数:8
相关论文
共 77 条
[1]  
Baumeister R, 1997, Genes Funct, V1, P149
[2]   Caspase-mediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signaling [J].
Brockhaus, M ;
Grünberg, J ;
Röhrig, S ;
Loetscher, H ;
Wittenburg, N ;
Baumeister, R ;
Jacobsen, H ;
Haass, C .
NEUROREPORT, 1998, 9 (07) :1481-1486
[3]   The proteolytic fragments of the Alzheimer's disease-associated presenilin-1 form heterodimers and occur as a 100-150-kDa molecular mass complex [J].
Capell, A ;
Grünberg, J ;
Pesold, B ;
Diehlmann, A ;
Citron, M ;
Nixon, R ;
Beyreuther, K ;
Selkoe, DJ ;
Haass, C .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (06) :3205-3211
[4]   Presenilin-1 differentially facilitates endoproteolysis of the β-amyloid precursor protein and Notch [J].
Capell, A ;
Steiner, H ;
Romig, H ;
Keck, S ;
Baader, M ;
Grim, MG ;
Baumeister, R ;
Haass, C .
NATURE CELL BIOLOGY, 2000, 2 (04) :205-211
[5]   Additive effects of PS1 and APP mutations on secretion of the 42-residue amyloid β-protein [J].
Citron, M ;
Eckman, CB ;
Diehl, TS ;
Corcoran, C ;
Ostaszewski, BL ;
Xia, WM ;
Levesque, G ;
Hyslop, PS ;
Younkin, SG ;
Selkoe, DJ .
NEUROBIOLOGY OF DISEASE, 1998, 5 (02) :107-116
[6]   Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice [J].
Citron, M ;
Westaway, D ;
Xia, WM ;
Carlson, G ;
Diehl, T ;
Levesque, G ;
JohnsonWood, K ;
Lee, M ;
Seubert, P ;
Davis, A ;
Kholodenko, D ;
Motter, R ;
Sherrington, R ;
Perry, B ;
Yao, H ;
Strome, R ;
Lieberburg, I ;
Rommens, J ;
Kim, S ;
Schenk, D ;
Fraser, P ;
Hyslop, PS ;
Selkoe, DJ .
NATURE MEDICINE, 1997, 3 (01) :67-72
[7]   An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos [J].
Davis, JA ;
Naruse, S ;
Chen, H ;
Eckman, C ;
Younkin, S ;
Price, DL ;
Borchelt, DR ;
Sisodia, SS ;
Wong, PC .
NEURON, 1998, 20 (03) :603-609
[8]   Alzheimer's disease -: Closing in on γ-secretase [J].
De Strooper, B .
NATURE, 2000, 405 (6787) :627-629
[9]   A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain [J].
De Strooper, B ;
Annaert, W ;
Cupers, P ;
Saftig, P ;
Craessaerts, K ;
Mumm, JS ;
Schroeter, EH ;
Schrijvers, V ;
Wolfe, MS ;
Ray, WJ ;
Goate, A ;
Kopan, R .
NATURE, 1999, 398 (6727) :518-522
[10]   Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein [J].
De Strooper, B ;
Saftig, P ;
Craessaerts, K ;
Vanderstichele, H ;
Guhde, G ;
Annaert, W ;
Von Figura, K ;
Van Leuven, F .
NATURE, 1998, 391 (6665) :387-390