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J Biol Chem, Vol. 274, Issue 34, 24007-24013, August 20, 1999

Interaction of Alzheimer's Presenilin-1 and Presenilin-2 with Bcl-X_L
A POTENTIAL ROLE IN MODULATING THE THRESHOLD OF CELL DEATH

Brent J. Passer, Luca Pellegrini, Pasquale Vito^§, J. Kelly Ganjei, and Luciano D'Adamio

From the  T Cell Apoptosis Unit, Laboratory of Cellular and Molecular Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892 and ^§ Basel Institute for Immunology, Grenzacherstrasse 487, Postfach CH-4005, Basel, Switzerland

The familial Alzheimer's disease gene products, presenilin-1 and presenilin-2, have been reported to be functionally involved in amyloid precursor protein processing, notch receptor signaling, and programmed cell death or apoptosis. However, the molecular mechanisms by which presenilins regulate these processes remain unknown. With regard to the latter, we describe a molecular link between presenilins and the apoptotic pathway. Bcl-X_L, an anti-apoptotic member of the Bcl-2 family was shown to interact with the carboxyl-terminal fragments of PS1 and PS2 by the yeast two-hybrid system. In vivo interaction analysis revealed that both PS2 and its naturally occurring carboxyl-terminal products, PS2short and PS2Ccas, associated with Bcl-X_L, whereas the caspase-3-generated amino-terminal PS2Ncas fragment did not. This interaction was corroborated by demonstrating that Bcl-X_L and PS2 partially co-localized to sites of the vesicular transport system. Functional analysis revealed that presenilins can influence mitochondrial-dependent apoptotic activities, such as cytochrome c release and Bax-mediated apoptosis. Together, these data support a possible role of the Alzheimer's presenilins in modulating the anti-apoptotic effects of Bcl-X_L.

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

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