Biology Reference
In-Depth Information
the ER. In this way, it has been reported that several FAD-linked presenilin
mutants altered the expression or sensitivity of the RyR and the IP3R in
different models, including cell lines, neurons and brain microsomes (
Matt-
son, 2010
). In parallel, it has also been proposed that the SERCA could
be a target for presenilins, although opposite regulatory effects have been
reported in this respect (
Green et al., 2008
;
Brunello et al., 2009
). Finally, Tu
et al. reported that WT presenilins form low-conductance calcium leak
channels in the ER membrane (
Tu et al., 2006
;
Nelson et al., 2007
). These
results favor the “calcium overload” hypothesis for FAD, which proposes
that the reduced ER calcium leak caused by FAD-linked presenilin mutants
results in increased ER-calcium concentrations and exaggerated calcium
release upon cell stimulation (
LaFerla, 2002
;
Thinakaran and Sisodia, 2006
).
However, among all these observations, the most important evidence for a
role of ER—and more specifically for MAM—in calcium dysregulation in
AD is the finding that PS1 and PS2 are able to directly interact with the
IP3R, and that FAD-linked mutants not only dramatically enhance the gat-
ing of the channel but also stimulate the production of Aβ (
Cheung et al.,
2008
,
2010
). More recently and reinforcing the same concept,
Zampese
et al. (2011)
, by directly measuring mitochondrial calcium dynamics, showed
that PS2, favors calcium transfer between ER and mitochondria, an effect
that was reduced by PS2 downregulation and enhanced by the expression
of PS2 mutants. However, how this transfer may modulate mitochondrial
function and neuronal metabolism is still a matter of debate.
Since mitochondria need to be strategically positioned at sites where
metabolic demand is high (
Zenisek and Matthews, 2000
;
Li et al., 2004
),
a problem with calcium handling not only would affect the control of
the mitochondrial functioning (through an imbalance in the control of
the Krebs cycle enzymes) but also would provoke alterations in the cal-
cium-mediated mitochondrial movement along axons, triggering highly
deleterious effects on neuronal function in general, and on synaptic trans-
mission in particular (as reported by
Stokin et al., 2005
;
Q. Wang et al.,
2008
,
2009a
;
2009b
). According to these data, it has been proposed that a
model of altered MAM function could provide a unifying hypothesis to
explain many of the features of the AD, including the elevated ratios of
Aβ
42
/Aβ
40
(via changes in the content of cholesterol), hyperphosphory-
lation of tau (via changes in the phospholipid metabolism) and aberrant
mitochondrial dynamics, with retention of large numbers of fragmented
mitochondria in the perinuclear region of cells (via abnormal calcium
transport between ER and mitochondria) (
Schon and Area-Gomez, 2010
).
Search WWH ::
Custom Search