A loss of function mutant of the presenilin homologue SEL-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increases Aβ42 generation in human cells
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 (beta APP). 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.
机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Brockhaus, M
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Grünberg, J
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Grünberg, J
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Röhrig, S
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Röhrig, S
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Loetscher, H
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Loetscher, H
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Wittenburg, N
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Wittenburg, N
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Baumeister, R
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Baumeister, R
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Jacobsen, H
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Jacobsen, H
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Haass, C
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F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, SwitzerlandF Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Brockhaus, M
;
Grünberg, J
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Grünberg, J
;
Röhrig, S
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Röhrig, S
;
Loetscher, H
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Loetscher, H
;
Wittenburg, N
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Wittenburg, N
;
Baumeister, R
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Baumeister, R
;
Jacobsen, H
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机构:F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland
Jacobsen, H
;
Haass, C
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F Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, SwitzerlandF Hoffmann La Roche & Co Ltd, Preclin CNS Res Gene Technol, Div Pharma, Basel, Switzerland