Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa C-terminal fragment are death substrates for proteases of the caspase family.
Mutations in the presenilin (PS) genes are linked to early onset familial Alzheimer's disease (FAD). PS-1 proteins are proteolytically processed by an unknown protease leading to the formation of two stable fragments of approximately 30 and approximately 20 kDa [Thinakaran, G., et al. (1996) Neuron 17, 181-190]. In addition to the conventional fragments, alternative cleavage products were observed as well. Here we characterize an alternative proteolytic pathway of PS-1 which involves proteases of the caspase superfamily. Caspase mediated cleavage occurs between aspartate 345 and serine 346 C-terminal to the conventional cleavage determined previously [Podlisny, M., et al., (1997) Neurobiol. Dis. 3, 325-337]. Full-length PS-1 can serve as a substrate for caspase-like proteases, as demonstrated by the generation of the alternative C-terminal fragment in cells expressing PS-1 containing the Deltaexon 10 deletion which is known to accumulate as a full-length molecule [Thinakaran, G., et al. (1996)]. By inhibition of de novo protein synthesis in untransfected cells we demonstrate that the conventional C-terminal fragment of PS-1 is a substrate for caspase-like proteases as well. Therefore full-length and the conventional C-terminal fragment of PS-1 can serve as potential death substrates. Due to the fact that very little full-length PS-1 is expressed in vivo, the much more abundant C-terminal fragment and not the full-length precursor is the major in vivo substrate for the alternative cleavage of PS-1 by proteases of the caspase superfamily.
Grunberg
J
J
Central Institute of Mental Health, Department of Molecular Biology, J5, 68159 Mannheim, Germany.
Walter
J
J
Loetscher
H
H
Deuschle
U
U
Jacobsen
H
H
Haass
C
C
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D016923:Cell Death; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational; D013379:Substrate Specificity
D017931:DNA Primers; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D003546:Cysteine Endopeptidases