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Medical Biotechnology Center of the University of Maryland Biotechnology Institute and Departments of Molecular Biology
and Biophysics, Neurology, and Human Genetics, Baltimore, Maryland 21201
Mutations in the genes for presenilin 1 and 2 (PS-1 and PS-2) have been linked to development of
early-onset Alzheimer's disease (AD). As neither the
normal function of either presenilin is known nor why
mutations cause disease, we examined the properties of wild-type, truncated, and mutant PS-2 upon expression
in HeLa cells. Although HeLa cells are strongly predisposed to continued mitosis, expression of PS-2 induced
programmed cell death (apoptosis). Direct evidence for
apoptosis was obtained by double staining for terminal
deoxynucleotide transferase nick end labeling
(TUNEL) and PS-2 expression and by following green
fluorescent protein-tagged PS-2 over time. Deletion
analysis indicates that as little as 166 NH2-terminal residues of PS-2 are sufficient for endoplasmic reticulum
(ER) localization and apoptosis. Moreover, the AD-
associated PS-2 missense mutation (N141I) more efficiently induced cell death compared to wild-type PS-2
despite lower mutant protein accumulation. Expression
of the presenilins in several other cell lines and transgenic mice has been accompanied by rapid protein
cleavage without the induction of cell death. In contrast, PS-2 expressed in HeLa cells was not cleaved, and
cell death occurred. We hypothesize that full-length but
not cleaved PS-2 may be important in the regulation or
induction of apoptosis.
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