A Loss of Function Mutant of the Presenilin Homologue SEL-12 Undergoes Aberrant Endoproteolysis in Caenorhabditis elegans and Increases Aβ42 Generation in Human Cells
| Autor: | Ralf Baumeister, Anja Capell, Andreas Böttcher, Masayasu Okochi, Helmut Romig, Jochen Walter, Christian Haass, Harald Steiner, Stefan Eimer |
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| Rok vydání: | 2000 |
| Předmět: |
Amyloid beta-Peptides
Receptors Notch Mutant Membrane Proteins Helminth Proteins Cell Biology Biology Cleavage (embryo) biology.organism_classification Biochemistry Molecular biology Presenilin Cell Line Cell culture Caspases Mutation Animals Humans Allele Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology Gene Loss function |
| Zdroj: | Journal of Biological Chemistry. 275:40925-40932 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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