title: A loss of function mutant of the presenilin homologue SEL-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increases abeta 42 generation in human cells.
abstract: The familial Alzheimer's disease-associated presenilins (PSs) occur as a dimeric complex of proteolytically generated fragments, which functionally supports endoproteolysis of Notch and the beta-amyloid precursor protein (betaAPP). A homologous gene, sel-12, has been identified in Caenorhabditis elegans. We now demonstrate that wild-type (wt) SEL-12 undergoes endoproteolytic cleavage in C. elegans similar to the PSs in human tissue. In contrast, SEL-12 C60S protein expressed from the sel-12(ar131) allele is miscleaved in C. elegans, resulting in a larger mutant N-terminal fragment. Neither SEL-12 wt nor C60S undergo endoproteolytic processing upon expression in human cells, suggesting that SEL-12 is cleaved by a C. elegans-specific endoproteolytic activity. The loss of function of sel-12 in C. elegans is not associated with a dominant negative activity in human cells, because SEL-12 C60S and the corresponding PS1 C92S mutation do not interfere with Notch1 cleavage. Moreover, both mutant variants increase the aberrant production of the highly amyloidogenic 42-amino acid version of amyloid beta-peptide similar to familial Alzheimer's disease-associated human PS mutants. Our data therefore demonstrate that the C60S mutation in SEL-12 is associated with aberrant endoproteolysis and a loss of function in C. elegans, whereas a gain of misfunction is observed upon expression in human cells.
authors.affiliation: Adolf Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's Disease Research, Ludwig-Maximilians-University, 80336 Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Okochi
authors.forename: S
authors.initials: S
authors.lastname: Eimer
authors.forename: A
authors.initials: A
authors.lastname: Bottcher
authors.forename: R
authors.initials: R
authors.lastname: Baumeister
authors.forename: H
authors.initials: H
authors.lastname: Romig
authors.forename: J
authors.initials: J
authors.lastname: Walter
authors.forename: A
authors.initials: A
authors.lastname: Capell
authors.forename: H
authors.initials: H
authors.lastname: Steiner
authors.forename: C
authors.initials: C
authors.lastname: Haass
mesh_terms: D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins; D020169:Caspases / Q000502:physiology; D002460:Cell Line; D015801:Helminth Proteins / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D051880:Receptors, Notch
chemical_list: D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; C095907:SEL-12 protein, C elegans; D020169:Caspases