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A historical overview of protein kinase PKR…
accumulated in degenerating neurons in the brain of
patients with AD (163). Moreover, a number of recent
studies have implicated PKR in the pathogenesis of other
neurodegenerative diseases, such as Parkinson's disease,
Huntington's disease, and amyotrophic lateral sclerosis
(164-166). Previously, it had been demonstrated that the
Aß peptide could induce PKR activation in primary
neuronal cultures, triggering cell death by apoptosis (131). deficient in the expression of PKR when subjected to a
Therefore, PKR activation was considered as a secondary
consequence of extracellular senile plaque formation
contributing to neuronal degeneration. However, recent
evidence indicates a direct involvement of PKR activation
in the pathology of the disease promoting BACE I
expression, an enzyme involved in the accumulation of Aß
peptide (131, 167). Moreover, PKR is also involved in the
mechanism of senile plaque formation through tau
phosphorylation via glycogen synthase kinase 3ß (GSK-
3ß) activation (168). On the other hand, PKR seems to be
involved in the inflammatory process that has been
suggested to contribute to AD (131, 169). Several works
have shown how PKR inhibition prevented the neuronal
loss by apoptosis, suggesting the high potential of PKR as
a therapeutic target in neurodegenerative diseases (131,
169). In addition, data showing PKR involvement in
learning and memory suggest that PKR inhibition could
benefit humans, especially those experiencing age-related
memory loss or the most devastating memory loss
associated with AD (170). Although different chemical
compounds and specific peptides protect neurons from
apoptosis by inhibiting PKR, unfortunately they also
display high toxicity, induce undesirable effects outside
the nervous system, or are not able to cross the blood brain evidence on the connection of PKR with these pathologies
barrier (131, 169). It is therefore necessary to continue
looking for new specific inhibitors of PKR. Due to the fact
that PKR is an ubiquitous and multifunctional protein, the
knowledge of the components involved in how and why
PKR is more active in these pathologies would help find
alternative drugs to target the abnormal activation of PKR
and contribute to the therapeutic control of
neurodegenerative diseases.
4.3. Is PKR involved in inflammatory diseases?
Since PKR is induced by IFNa and the
proinflammatory NF-kB transcription factor is a target of
the kinase, its involvement in inflammatory processes has
been suggested in several works (1, 2). In fact,
experiments using primary mouse cocultures containing
neurons, astrocytes, and microglia have shown that
inhibition of PKR prevents activation of NF-kB, as well as
a strong decrease in production and release of tumour
necrosis factor-a (TNF-a) and interleukin-1b (IL-1b),
(171). Several studies have shown a significant increase in
various inflammatory mediators in plasma and peripheral
blood mononuclear cells of patients with AD compared to
age-matched controls (172). Interestingly, levels of both
total PKR and phospho-PKR were modified in blood
lymphocytes of patients with AD compared with control
individuals, and the upregulation of these proteins in
cerebrospinal fluid was suggested as a potential biomarker
@Real Academia Nacional de Farmacia. Spain
for AD (131, 169).
Moreover, NFkB regulates the cytokines involved in
several inflammatory diseases like rheumatoid arthritis and
lupus erythematosus, such as IL-6, TNF-a, and IL-1. The
kinase PKR has been involved in the induction of TNF-a
and IL-6 in response to lipopolysaccharide (LPS) in
fibroblasts and alveolar macrophages (173). Interestingly,
transcription of IL-1ß, TNF-a and IL-6 decreased in mice
high-fat diet (174). The inhibition of PKR with the C16
compound in PBMCs isolated from patients significantly
decreased the expression and production of cytokines IL-
1ß, TNF-a, and IL-6, suggesting that the inhibition of PKR
at the peripheral level can decrease the inflammatory
process in Alzheimer's patients (172). However, the effect
of PKR inhibition over these cytokines in autoimmune
diseases has not yet been explored.
Recently, it has been shown that PKR is an important
key element of the inflammasome complex in
macrophages. PKR interacts with the NOD-like receptor
family, which, together with caspase 1 (Casp-1), integrates
this interesting complex, inducing high levels of the
HMGB1 cytokine (175). High levels of this cytokine and
of IL -1ß have also been linked with inflammatory
processes involved in AD, autoimmune diseases, and
cancer (131). In addition, the PKR gene deletion, or
specific drug inhibition, severely diminished
inflammasome activation in response to various stimuli
(131). Therefore, the analysis of PKR in cancer,
neurodegeneration, and autoimmune diseases in the
context of the inflammasome complex can provide new
with an interesting therapeutic potential.
5. CONCLUDING REMARKS AND FUTURE
PROSPECTS
Since PKR was discovered, its mechanism of action
has been gradually brought to light in several international
publications, an effort to which we have made important
contributions. The involvement of PKR in interferon-
mediated activities, in the induction of apoptosis, in the
activation of proinflammatory transcription factor NFkB,
along with its role in signalling pathways linking
numerous biological events which include antiviral
defence and cell growth, are clear indicators of the great
potential that this protein may have in a variety of
pathologies (Figure 7). The identification of PKR as a
target of both conventional chemotherapeutic and novel
drugs highlights the need to carry out translational studies
with patients to validate its potential as a biomarker of
important diseases like cancer and neurodegeneration.
Moreover, the PKR deregulation showed in diseases like
Alzheimer and inflammatory processes underlines the need
to find applicable inhibitors of this kinase. Since PKR is
expressed in almost all cells, its therapeutic potential could
arise from the factors involved in its regulation. In fact,
understanding the cellular factors and signals that regulate
the role of PKR in the different diseases would be
extremely valuable from a clinical point of view.
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