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Notably all these metabolic and morphological features have been found in
both FAD and SAD ( Wang et al., 2009b ), pointing to the MAM hypothesis
as a unifying explanation able to relate previously unconnected phenotypes.
Another interesting example is the pathogenesis of prion disease (PrD)
where several groups have reported the occurrence of ER stress responses,
including the activation of UPR transcription factor XBP1 splicing ( Hetz
et al., 2008 ) as well as JNK and ERK ( Steele et al., 2007 ; Hetz et al., 2008 ). In
Creutzfeldt-Jakob disease (CJD) patients and in some mouse models, upreg-
ulation of several chaperones and foldases such as BiP/GRP78, GRP94 and
GRP58/ERp57 is observed, which suggests abnormal ER homeostasis ( Yoo
et al., 2002 ; Hetz et al., 2003 , 2005 ; Brown et al., 2005 ; Rane et al., 2008 ).
These kinds of perturbations lead to the generation of intermediary mis-
folded forms of the cellular prion protein (PrPc) increasing its susceptibility
to convert into the PrP protease resistant form (PrP RES ) in vitro ( Apodaca
et al., 2006 ; Orsi et al., 2006 ). Moreover, recently, Hetz's group described the
contribution of calcium as another element in the development of infectious
and familial PrD ( Torres et al., 2010 ). Using purified PrP RES from the brain
of scrapie-infected mice, they evaluated its impact on ER stress responses and
calcium homeostasis. They found that the acute exposure of PrP RES to Neu-
ro2a cells induces release of calcium from the ER and ER stress, associated
with the upregulation of several chaperones and foldases including ERp57,
BiP/GRP78 and GRP94. Consistent with these results, cells chronically
infected with scrapie prions also display altered ER calcium levels. Addi-
tionally, scrapie-infected cells are more susceptible to undergo ER stress-
mediated cell death, associated with stronger UPR activation after exposure
to different ER stress-inducing agents ( Torres et al., 2010 ). The exact mecha-
nisms involved in calcium disturbance and how this directly affects neuronal
metabolism remain to be determined.
As a last example, in the fatal neurodegenerative disease amyotrophic lat-
eral sclerosis (ALS), motor neurons degenerate with signs of organelle frag-
mentation, free radical damage, mitochondrial calcium overload, impaired
axonal transport and accumulation of proteins in intracellular inclusion bod-
ies ( Grosskreutz et al., 2010 ). In ALS, chronic excitotoxicity mediated by
calcium-permeable AMPA-type glutamate receptors seems to initiate a self-
perpetuating process of intracellular calcium dysregulation with consecutive
ER calcium depletion and mitochondrial calcium overload. In this context,
Berridge et al. had postulated a model based on the chronic shift of calcium
from the ER compartment to mitochondria, inducing a long-term accumu-
lation of misfolded proteins in the ER due to a chronically low intraluminal
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