direct role of wild-type PS1 in the UPR. An inability of neurons expressing AD
presenilin mutants to mount a UPR would be expected to increase the vulnerability
of these cells to undergo apoptosis in response to ER stress or other stress signals.
Along this line, it is interesting that ER stress has been implicated in Aβ neurotoxicity,
since cortical neurons from caspase-12-deficient mice are resistant to Aβ-induced cell
death (Nakagawa et al., 2000). Furthermore, PS1 and PS2 can bind m-calpain and
inhibit its activation, and presenilin mutants lose this phenotype (Maruyama et al.,
2000), suggesting that, in some forms of AD, Aβ plaques could lead to increased
calpain-dependent activation of caspase-12 and apoptosis. Therefore, presenilin
mutations that lead to AD may not only increase the production of Aβ, but also
sensitize neurons to the toxic effects of this peptide by deregulating Ca2+ homeostasis,
preventing UPR survival signals, and by increasing calpain-mediated activation of
caspase-12.
5.
Concluding remarksIntensive research into the role of mitochondria in apoptosis has revealed
mitochondrial dysfunction as an essential component of almost all apoptotic
pathways. Bcl-2 proteins are unquestionably the key guardians of mitochondria
during apoptosis. Release of IMS proteins occurs when proapoptotic BH3-only and
BAX/BAK proteins overcome the protective effects of antiapoptotic Bcl-2 proteins.
Most models of Cyt.c release, however, stem from studies testing the effect of high
concentrations of recombinant Bcl-2 family members on isolated mitochondria,
where the dynamic nature of the mitochondrial network and its contacts with the
ER and cytoskeleton are lost, or the effect of overexpression of Bcl-2 family members
in intact cells, which represents a state of activation that these proteins are normally
unlikely to achieve. Moreover, experiments in cultured cells that are overstimulated
with high concentrations of apoptotic agents are probably poor representations of
the delicate balance between prolife and prodeath switches that exist within the tissues
of an organism. In these settings, proapoptotic Bcl-2 proteins are unlikely to function
in isolation since the activation of proapoptotic BH3-only proteins may be
suboptimal, and their ability to transform the mitochondria into a Cyt.c release-
competent state may be largely dependent on the alliance with other costimulatory
signals, which are also subject to positive or negative regulation. In this context,
independent Ca2+ signals from the ER (and perhaps other modulators originating
from the ER) may represent a critical determinant of how mitochondria respond to
proapoptotic stimuli in physiologic circumstances.
Is the ER always working just to influence mitochondrial transition during
apoptosis or can it function as a central integrator, like the mitochondria, in some
pathways? In the case of ER stress, where the death signal originates within the ER
itself, it is clear that the ER possesses its own set of apoptotic accessories to initiate
several cell-death signals. Future studies should shed light on whether these ER
signals, or other novel ER localized regulators, function in cell-death pathways
118 GENETICS OF APOPTOSIS