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Human Molecular Genetics Advance Access published online on May 5, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh151
© 2004 by Oxford University Press
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Article

Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice

Jos Tournoy 1, Xavier Bossuyt 2, An Snellinx 3, Marleen Regent 3, Marian Garmyn 4, Lutgarde Serneels 3, Paul Saftig 5, Katleen Craessaerts 3, Bart De Strooper 3, Dieter Hartmann 3*

1 Neuronal Cell Biology Laboratory, Center for Human Genetics CB 4, Catholic University of Leuven and Flanders Institute for Biotechnology VIB IV, Herestraat 49, B-3000 Leuven, Belgium; Aspirant of the Fund for Scientific Research of Flanders (FWO)
2 Dept. for Laboratory Medicine, University Hospital, Catholic University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
3 Neuronal Cell Biology Laboratory, Center for Human Genetics CB 4, Catholic University of Leuven and Flanders Institute for Biotechnology VIB IV, Herestraat 49, B-3000 Leuven, Belgium
4 Department for Dermatology, Catholic University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
5 Department for Biochemistry, CAU Kiel, Olshausenstrasse 40, D-24118 Kiel, FRG

* To whom correspondence should be addressed. E-mail: Dieter.Hartmann{at}med.kuleuven.ac.be.


  Abstract

Presenilins (PSs) 1 and 2 are the center of {gamma}-secretase that releases A{beta} from APP in Alzheimer's disease. They cleave signaling proteins like Notch and downregulate {beta}-catenin to modulate Wnt signaling. Inactivation of PS1 or PS1 and PS2 causes a prenatally lethal ‘Notch phenotype’, which has seriously hampered investigation of PS function in adulthood. We have thus turned towards PS1+/- PS2-/- mice that carry the most severe reduction of PS alleles compatible with survival to analyze the consequences of impaired PS function especially in adulthood.

In these ‘partial deficient’ mice PS1 protein concentration is considerably lowered, functionally reflected by reduced {gamma}-secretase activity and impaired {beta}-catenin downregulation. Their phenotype is normal up to about 6 months, when the majority of the mice develop an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis and vasculitis, as seen in human systemic lupus erythematosus. Besides B-cell dominated infiltrates, we observe a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies and an increased CD4+/CD8+ ratio. The mice further develop a benign skin hyperplasia similar to human seborrheic keratosis as opposed to malignant keratocarcinomata observed in skin-specific PS1 ‘full’ knockouts.

A partial reduction of PS function in PS1+/-PS2-/- mice causes a novel phenotype in adulthood unrelated to the developmental defects of ‘full’ knockouts. As PS1+/-PS2+/- mice remain healthy, this points towards a sharply defined minimum of PS function. Skin and immune system appear as especially sensitive targets of impaired PS function and may need careful monitoring if {gamma}-secretase inhibitors are envisaged for treating AD.


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