Caspase-mediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signaling.
The Alzheimer's disease (AD) associated presenilin (PS) proteins are proteolytically processed. One of the processing pathways involves cleavage by caspases. Pharmacological inhibition of caspases is currently being discussed as a treatment for a variety of neurodegenerative diseases, including AD. We therefore inhibited caspase mediated processing of PS-1 and PS-2 in cells transfected with wt and mutant PS by mutagenizing the substrate recognition site or by using specific peptide aldehydes known to block caspases. We found that the inhibition of caspase mediated processing of PS proteins does not decrease its amyloidogenic activity. PS cDNA constructs with mutations in the caspase cleavage site are biologically active in Caenorhabditis elegans such as the wt human PS proteins, demonstrating that caspase-mediated cleavage is not required for the physiological PS function in NOTCH signaling.
Brockhaus
M
M
F. Hoffmann-LaRoche Ltd, Pharma Division, Preclinical CNS Research-Gene Technology, Basel, Switzerland.
Grünberg
J
J
Röhrig
S
S
Loetscher
H
H
Wittenburg
N
N
Baumeister
R
R
Jacobsen
H
H
Haass
C
C
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites; D017173:Caenorhabditis elegans; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009447:Neuroblastoma; D010957:Plasmids; D017354:Point Mutation; D053764:Presenilin-1; D053766:Presenilin-2; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011994:Recombinant Proteins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases