A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity.
Mutations in presenilin-1 and presenilin-2 (PS1 and PS2) are the most common cause of familial Alzheimer disease. PS1 and PS2 are the presumptive catalytic components of the multisubunit gamma-secretase complex, which proteolyzes a number of type I transmembrane proteins, including the amyloid precursor protein (APP) and Notch. APP processing by gamma-secretase produces beta-amyloid peptides (Abeta40 and Abeta42) that accumulate in the Alzheimer disease brain. Here we identify a pathogenic L435F mutation in PS1 in two affected siblings with early-onset familial Alzheimer disease characterized by deposition of cerebral cotton wool plaques. The L435F mutation resides in a conserved C-terminal PAL sequence implicated in active site conformation and catalytic activity. The impact of PS1 mutations in and around the PAL motif on gamma-secretase activity was assessed by expression of mutant PS1 in mouse embryo fibroblasts lacking endogenous PS1 and PS2. Surprisingly, the L435F mutation caused a nearly complete loss of gamma-secretase activity, including >90% reductions in the generation of Abeta40, Abeta42, and the APP and Notch intracellular domains. Two nonpathogenic PS1 mutations, P433L and L435R, caused essentially complete loss of gamma-secretase activity, whereas two previously identified pathogenic PS1 mutations, P436Q and P436S, caused partial loss of function with substantial reductions in production of Abeta40, Abeta42, and the APP and Notch intracellular domains. These results argue against overproduction of Abeta42 as an essential property of presenilin proteins bearing pathogenic mutations. Rather, our findings provide support for the hypothesis that pathogenic mutations cause a general loss of presenilin function.
Heilig
Elizabeth A
EA
Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Xia
Weiming
W
Shen
Jie
J
Kelleher
Raymond J
RJ
D017668:Age of Onset; D000544:Alzheimer Disease / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D019943:Amino Acid Substitution / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D008875:Middle Aged; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D058225:Plaque, Amyloid / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D053764:Presenilin-1 / Q000172:deficiency / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D051880:Receptors, Notch / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D015820:Cadherins; D050505:Mutant Proteins; D053764:Presenilin-1; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases
Cell. 2007 Oct 19;131(2):215-21
17956719
J Biol Chem. 1999 Mar 19;274(12):7615-8
10075646
Neurosci Res. 2007 Mar;57(3):446-53
17210196
J Neurosci. 2008 Jun 11;28(24):6264-71
18550769
Biochemistry. 2002 Mar 12;41(10):3372-9
11876645
J Neurochem. 2006 Jan;96(1):218-27
16305624
J Biol Chem. 2008 Oct 31;283(44):29627-31
18650432
J Neurochem. 2006 May;97(4):1052-6
16606360
J Neurosci. 1997 Sep 15;17(18):7053-9
9278541
Ann Neurol. 2000 Nov;48(5):806-8
11079548
Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):11872-7
10518543
Science. 2001 May 25;292(5521):1550-2
11375493
Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):403-9
17197420
J Neurosci. 2000 Dec 1;20(23):8717-26
11102478
Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14940-4
8962160
Neuron. 2004 Apr 8;42(1):23-36
15066262
Curr Opin Neurol. 2000 Aug;13(4):377-84
10970053
Neurodegener Dis. 2005;2(1):6-15
16908998
Biochemistry. 2001 Apr 24;40(16):5049-55
11305921
J Neurochem. 2005 May;93(4):769-92
15857382
J Neurosci. 2005 Jul 20;25(29):6755-64
16033885
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13075-80
14566063
Neurosci Lett. 2006 Jul 24;402(3):278-83
16687212
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4119-24
10097173
Hum Mutat. 2006 Jul;27(7):686-95
16752394
Biochemistry. 1999 Apr 13;38(15):4720-7
10200159
Science. 2002 Jul 19;297(5580):353-6
12130773
J Biol Chem. 2002 May 24;277(21):19236-40
11943765
Nat Med. 1998 Apr;4(4):452-5
9546792
Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R201-6
12966028
J Biol Chem. 2006 Oct 20;281(42):31279-89
16899457
J Cell Sci. 1998 Dec 18;111 ( Pt 24):3645-54
9819355
J Biol Chem. 2001 Aug 31;276(35):33273-81
11432849
Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8025-30
12048239
J Neurosci. 1999 Oct 1;19(19):8435-42
10493744
J Neurochem. 2008 Feb;104(3):573-83
17995932
J Cell Sci. 2003 Mar 15;116(Pt 6):1127-36
12584255
J Neurosci. 2002 May 1;22(9):3445-53
11978821
Neuron. 2005 May 19;46(4):541-54
15944124
J Biol Chem. 2004 Aug 27;279(35):36519-29
15220354
J Neurochem. 2005 Jan;92(2):294-301
15663477
J Biol Chem. 2005 May 13;280(19):19070-7
15764596
Nat Rev Neurosci. 2008 Oct;9(10):768-78
18802446
Science. 1996 Oct 4;274(5284):99-102
8810256
J Biol Chem. 2003 Jul 4;278(27):24294-301
12707272
Neurobiol Aging. 2004 Aug;25(7):885-92
15212842
Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13170-5
8917563
J Biol Chem. 2003 Feb 28;278(9):6748-54
12493737
Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1683-8
8643690
J Biol Chem. 2006 Jun 2;281(22):15330-6
16574645
Neurology. 2001 Aug 28;57(4):621-5
11524469
J Neurochem. 2006 Feb;96(3):732-42
16405513
J Biol Chem. 2002 Sep 27;277(39):36521-6
12119298
J Biol Chem. 1999 Jul 16;274(29):20499-504
10400678
EMBO Rep. 2007 Feb;8(2):136-40
17268504
J Biol Chem. 2008 Jul 11;283(28):19793-803
18482978
Neurobiol Dis. 2004 Apr;15(3):654-66
15056474
Nat Med. 2000 Feb;6(2):143-50
10655101