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J Biol Chem, Vol. 274, Issue 12, 7615-7618, March 19, 1999

COMMUNICATION
The Biological and Pathological Function of the Presenilin-1 Exon 9 Mutation Is Independent of Its Defect to Undergo Proteolytic Processing

Harald Steiner, Helmut Romig^§, Melissa G. Grim^¶, Uwe Philipp^§, Brigitte Pesold, Martin Citron, Ralf Baumeister^¶, and Christian Haass

From the  Central Institute of Mental Health, Department of Molecular Biology, J5, 68159 Mannheim, Germany, ^§ Boehringer Ingelheim KG, CNS Research, 55216 Ingelheim, Germany, ^¶ Genzentrum, Feodor-Lynen-Str.25, 81377 Munich, Germany, and  Amgen Inc., Thousand Oaks, California 91320-1789

The two homologous presenilins are key factors for the generation of amyloid -peptide (A), since Alzheimer's disease (AD)-associated mutations enhance the production of the pathologically relevant 42-amino acid A (A42), and a gene knockout of presenilin-1 (PS1) significantly inhibits total A production. Presenilins undergo proteolytic processing within the domain encoded by exon 9, a process that may be closely related to their biological and pathological activity. An AD-associated mutation within the PS1 gene deletes exon 9 (PS1exon9) due to a splicing error and results in the accumulation of the uncleaved full-length protein. We now demonstrate the unexpected finding that the pathological activity of PS1exon9 is independent of its lack to undergo proteolytic processing, but is rather due to a point mutation (S290C) occurring at the aberrant exon 8/10 splice junction. Mutagenizing the cysteine residue at position 290 to the original serine residue completely inhibits the pathological activity in regard to the elevated production of A42. Like PS1exon9, the resulting presenilin variant (PS1exon9 C290S) accumulates as an uncleaved protein and fully replaces endogenous presenilin fragments. Moreover, PS1exon9 C290S exhibits a significantly increased biological activity in a highly sensitive in vivo assay as compared with the AD-associated mutation. Therefore not only the increased A42 production but also the decreased biological function of PS1exon9 is due to a point mutation and independent of the lack of proteolytic processing.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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