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induction and cardiac metabolism is an issue that requires more attention to
understand how contractile dysfunction and cell death ensue.
6.3. UPR and Neurodegeneration
In neurons and in several models of neurodegenerative diseases, calcium
plays a critical role as a second messenger, controlling synaptic function
and cell viability. In basal cellular conditions, ER calcium concentrations
are close to 300 µM, whereas cytosolic calcium concentrations usually range
between 5 and 50 nM ( Pozzan et al., 1994 ). Several key ER chaperones
require optimal calcium concentrations for their protein folding activity,
pointing to ER-calcium depletion as an important target in the folding and
maturation of proteins and as a key element in the development of some
neurodegenerative diseases where the folding capacity of the neurons is
challenged ( Corbett et al., 1999 ; Ashby and Tepikin, 2001 ). Additionally, a
sustained increase in the cytosolic calcium may also induce mitochondria-
mediated apoptosis via the activation of proteins like calcineurin or by an
overload of mitochondrial calcium ( Wang et al., 1999 ). Moreover, recent
findings correlate ER stress with the control of mitochondrial function and
metabolism through mechanisms involving calcium transfer from the ER
to mitochondria ( Cárdenas et al., 2010 ; Troncoso et al., 2011 ; Bravo et al.,
2011a , 2011b ). For all these reasons, regulation of the calcium concentration
in the cytosol and ER are critical for maintaining normal neuronal function
and homeostasis.
One critical example is AD, one of the most common forms of dementia
in developed countries, where defects in calcium signaling due to altered ER
(specifically MAM) function could explain the well-known disturbances
in calcium homeostasis and mitochondrial deficits observed in this disease
( Smith et al., 2005 ; Small, 2009 ; Yu et al., 2009 ), including the enhanced IP3-
mediated release of calcium in fibroblasts from patients with the sporadic
(SAD) (114) or the familial (FAD) form of the Alzheimer disease ( Ito et al.,
1994 ; Leissring et al., 1999a , 1999b ; Nelson et al., 2007 ). The majority of
FAD cases are caused by point mutations in the genes of two homologous
proteins, presenilin 1 (PS1) and presenilin 2 (PS2), essential components
of the γ-secretase complex responsible for the production of the amyloid
β peptides (Aβ) ( Goedert and Spillantini, 2006 ) that mainly localize to at
the MAM surface ( Schon and Area-Gomez, 2010 ). Accumulating evidence
suggests that FAD is linked to an imbalance of cellular calcium homeosta-
sis ( Bojarski et al., 2008 ; Mattson, 2010 ) and, in particular, the presenilins
appear to play a key role in the control of calcium concentration within
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