Journal Article

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

Jos Tournoy, Xavier Bossuyt, An Snellinx, Marleen Regent, Marian Garmyn, Lutgarde Serneels, Paul Saftig, Katleen Craessaerts, Bart De Strooper and Dieter Hartmann

in Human Molecular Genetics

Volume 13, issue 13, pages 1321-1331
Published in print July 2004 | ISSN: 0964-6906
Published online May 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh151
Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice

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Presenilin (PS1) and (PS2) are the centers of γ-secretase that release Aβ from APP in Alzheimer's disease (AD). They cleave signaling proteins like Notch and downregulate β-catenin to modulate Wnt signaling. Inactivation of PS1 or PS1 and PS2 causes a prenatally lethal ‘Notch phenotype,’ which has hampered investigation of PS function in adulthood seriously. We have thus turned towards PS1+/−PS2−/− mice which 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 γ-secretase activity and impaired β-catenin downregulation. Their phenotype is normal up to ∼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 to be especially sensitive targets of impaired PS function and may need careful monitoring if γ-secretase inhibitors are envisaged for treating AD.

Journal Article.  6275 words.  Illustrated.

Subjects: Genetics and Genomics

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