Alzheimer's disease-linked mutation of presenilin 2 (N141I-PS2) drastically lowers APPalpha secretion: control by the proteasome.
Most of early onset familial forms of Alzheimer's disease (FAD) are due to inherited mutations located on two homologous proteins, presenilins 1 and 2 (PS1 and PS2) encoded by chromosomes 14 and 1, respectively. Here we show that the expression of wild type (wt)-PS2 in human HEK293 cells increases the production of the physiological alpha-secretase-derived product, APPalpha. By contrast, APPalpha secretion is drastically reduced in cells expressing the FAD-linked N141I-PS2. We establish that wt-PS2, N141I-PS2 and their C-terminal maturation fragment are degraded by the enzymatic multicatalytic complex, proteasome. Interestingly, two selective proteasome inhibitors, Z-IE(Ot-Bu)A-Leucinal and lactacystin potentiate the APPalpha secretion observed in wtPS2-expressing cells and further amplify the N141I-PS2-induced decrease in APPalpha production. By contrast, a series of pharmacological agents unable to affect the proteasome do not modify PS2 immunoreactivities and APPalpha recoveries. Altogether, our data indicate that: 1) wtPS2 positively modulates the alpha-secretase physiological pathway of betaAPP maturation in human cells; 2) N141I mutation on PS2 drastically lowers the secretion of APPalpha; 3) Proteasome inhibitors prevent the degradation of wtPS2, N141I-PS2 and their C-terminal maturation product. This protection against proteasomal degradation directly modulates the APPalpha secretion response elicited by wt- and FAD-linked PS2 expression in human HEK293 cells.
Marambaud
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Institut de Pharmacologie Moléculaire et Cellulaire, du CNRS, UPR411, 660 Route des Lucioles, Sophia Antipolis, Valbonne, 06560, France.
Alves da Costa
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Ancolio
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Checler
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D000544:Alzheimer Disease / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D007668:Kidney; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D009097:Multienzyme Complexes / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D053766:Presenilin-2; D046988:Proteasome Endopeptidase Complex; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D015853:Cysteine Proteinase Inhibitors; D008565:Membrane Proteins; D009097:Multienzyme Complexes; C508861:PSEN2 protein, human; D053766:Presenilin-2; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D046988:Proteasome Endopeptidase Complex