Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms.
Mutations in human presenilin (PS) genes cause aggressive forms of familial Alzheimer's disease. Presenilins are polytopic proteins that harbour the catalytic site of the gamma-secretase complex and cleave many type I transmembrane proteins including beta-amyloid precursor protein (APP), Notch and syndecan 3. Contradictory results have been published concerning whether PS mutations cause 'abnormal' gain or (partial) loss of function of gamma-secretase. To avoid the possibility that wild-type PS confounds the interpretation of the results, we used presenilin-deficient cells to analyse the effects of different clinical mutations on APP, Notch, syndecan 3 and N-cadherin substrate processing, and on gamma-secretase complex formation. A loss in APP and Notch substrate processing at epsilon and S3 cleavage sites was observed with all presenilin mutants, whereas APP processing at the gamma site was affected in variable ways. PS1-Delta9 and PS1-L166P mutations caused a reduction in beta-amyloid peptide Abeta40 production whereas PS1-G384A mutant significantly increased Abeta42. Interestingly PS2, a close homologue of PS1, appeared to be a less efficient producer of Abeta than PS1. Finally, subtle differences in gamma-secretase complex assembly were observed. Overall, our results indicate that the different mutations in PS affect gamma-secretase structure or function in multiple ways.
Bentahir
Mostafa
M
Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB4) and K. U. Leuven, Leuven, Belgium.
Nyabi
Omar
O
Verhamme
Jan
J
Tolia
Alexandra
A
Horré
Katrien
K
Wiltfang
Jens
J
Esselmann
Hermann
H
De Strooper
Bart
B
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D029721:Drosophila Proteins; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D004622:Embryo, Mammalian; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016296:Mutagenesis / Q000502:physiology; D009154:Mutation; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1; D040081:Protein Array Analysis / Q000379:methods; D011509:Proteoglycans / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D053667:Syndecans
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015820:Cadherins; C108740:Chi protein, Drosophila; D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D011509:Proteoglycans; D051880:Receptors, Notch; D053667:Syndecans; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse