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Journal of Signal Transduction
Volume 2012, Article ID 649079, 12 pages
doi:10.1155/2012/649079
Review Article
The Role of p38 MAPK and Its Substrates in Neuronal Plasticity
and Neurodegenerative Disease
Sˆ
onia A. L. Corrˆ
ea and Katherine L. Eales
School of Life Sciences, The University of Warwick, Coventry CV4 7AL, UK
Correspondence should be addressed to Sˆ
onia A. L. Corrˆ
ea, s.a.l.correa@warwick.ac.uk
Received 5 March 2012; Accepted 10 May 2012
Academic Editor: J. Simon C. Arthur
Copyright © 2012 S. A. L. Corr ˆ
ea and K. L. Eales. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
A significant amount of evidence suggests that the p38-mitogen-activated protein kinase (MAPK) signalling cascade plays a crucial
role in synaptic plasticity and in neurodegenerative diseases. In this review we will discuss the cellular localisation and activation
of p38 MAPK and the recent advances on the molecular and cellular mechanisms of its substrates: MAPKAPK 2 (MK2) and tau
protein. In particular we will focus our attention on the understanding of the p38 MAPK-MK2 and p38 MAPK-tau activation axis
in controlling neuroinflammation, actin remodelling and tau hyperphosphorylation, processes that are thought to be involved in
normal ageing as well as in neurodegenerative diseases. We will also give some insight into how elucidating the precise role of p38
MAPK-MK2 and p38 MAPK-tau signalling cascades may help to identify novel therapeutic targets to slow down the symptoms
observed in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease.
1. Introduction
The MAPKs are a specific class of serine/threonine kinases
which respond to extracellular signals such as growth factors,
mitogens, and cellular stress and mediate proliferation, dif-
ferentiation, and cell survival in mammalian cells. There are
4 distinct groups of MAPKs within mammalian cells: the
extracellular signal-related kinases (ERKs), the c-jun N-
terminal kinases (JNKs), the atypical MAPKs (ERK3, ERK5,
and ERK8), and the p38 MAPKs [1]. The p38 MAPKs are
described as stress-activated protein kinases as they are pri-
marily activated through extracellular stresses and cytokines
and consequently have been extensively studied in the field
of inflammation. There are, however, numerous additional
roles of p38 MAPK which are becoming of interest, including
the role that the p38 MAPK signalling pathway plays in
neuronal function such as synaptic plasticity and neurode-
generative disease.
In the present paper we will give an overview of p38
MAPK localisation, activation, and the functional role of
this signalling cascade in the mammalian brain, especially
the activation of the p38 MAPK cascade during synaptic
plasticity in the hippocampus. Although p38 MAPK iso-
forms have been shown to be highly expressed in the
brain, only a handful of brain-specific substrates for p38
MAPK have been characterised in vivo. In this paper we will
especially focus our attention on the role of two p38 MAPK
substrates in neurons: MAPK-activated protein kinase 2
(MAPKAPK-2, also known as MK2) and tau protein. The
involvement of the p38 MAPK-MK2 and p38 MAPK-tau
signalling cascades in neuroinflammation, actin remodeling,
and tau hyperphosphorylation in neurodegenerative diseases
will also be discussed. Highlighting the functional role of
specific p38 MAPK substrates in neurodegenerative disease
will be of particular importance as these could be potential
signalling targets which could be exploited therapeutically
to slow cognitive decline occurring in normal ageing and in
neurodegenerative disease.
2. Localisation and Activation of the p38 MAPK
Signalling Cascade in Mammalian Cells
The cascade of events leading to p38 MAPK activation is
highly conserved throughout mammalian tissues including
neuronal cells (Figures 1(a) and 1(b)). Similar to other
MAPKs, the p38 MAPK enzyme is activated by dual
phosphorylation of the threonine (Thr) and tyrosine (Tyr)
2Journal of Signal Transduction
(a) (b)
TKR
ASK-1
p38 MAPK
MKK 3/6
Rap 1
G-protein
?
TRAF 2/6
IRAK
TAK 1
Cytokines
Stress factors
GI-mGluR
Glutamate
?
Neuroinflammation
NMDAR
AMPAR
TLR
TNFR
ll-1R1
GluN1
GluN2
GluA1
GluA2
GluA2
GluA1
Figure 1: Signalling pathways leading to the activation of p38 MAPK in neurons. (a) Inflammatory cytokines bind to specific receptors at the
cell surface, which initiate a cascade of events promoting the activation of interleukin-1 receptor-associated kinase (IRAK), TNF receptor-
associated factor (TRAF) 2/6 leading to the activation of MKKKs (TAK 1, ASK-1), and subsequently phosphorylation of MKK3 and MKK6,
the upstream activators of p38 MAPK. (b) Release of glutamate from the presynaptic terminal can also activate p38 MAPK via a similar
route. Binding of glutamate by the postsynaptic GI-mGluR receptors causes the activation of G-proteins, which promote the exchange of
GDP with GTP of Rap 1. Rap 1 then initiates a cascade leading to the phosphorylation of MKK3/6 and p38 MAPK. The steps linking p38
MAPK activation to the internalisation of AMPA receptor (AMPAR) subunits observed during mGluR induced long-term depression are
not yet known. Reports have suggested that binding of glutamate to NMDA receptors (NMDARs) also activates p38 MAPK. However, the
molecular mechanism linking NMDAR activation to p38 MAPK phosphorylation is not yet known. The activated p38 MAPK signalling
cascade has been shown to regulate AMPAR trafficking; however no substrate for this regulation has been described.
residues in the Thr-Gly-Tyr (TGY) motif situated within
the kinase activation loop. Dual phosphorylation at Thr-
180 and Tyr-182 residues, by either MAP kinase kinase 3
(MKK3) or MAP kinase kinase 6 (MKK6), induces global
conformational reorganisations that modify the alignment of
the C- and N-terminal domains of p38 MAPK, consequently
permitting the binding of ATP and the desired substrate
[2]. The subcellular localisation of the p38 MAPK activators
MKK3 and MKK6 has been shown using an antibody against
a specific peptide present in either MKK3 or MKK6 in
addition to overexpression of wild-type MKK3 and MKK6-
FLAG-tagged proteins. These in vitro experiments in 293T
HEK cells showed a similar distribution profile for both
the endogenous and exogenous MKK3 and MKK6 proteins
in that they are both nuclear and cytoplasmically localised
within the cell [3]. The MAP kinase kinase kinases (MKKKs),
which are the upstream activators of the MKKs, have been
shown in HeLa cells to be activated and localised at the
plasma membrane and in the cytoplasm [4]. The subcellular
distribution of the upstream activators is therefore consistent
with their ability to activate p38 MAPK located either in
the cytoplasm as well as in the nucleus. Indeed in resting
cells, including cultured hippocampal neurons, p38 MAPK
protein is distributed throughout the cytoplasm and nucleus
(SAL Corrˆ
ea; unpublished data, [1]).
Mammalian cells are known to express four different
genes encoding p38 MAPK isoforms (p38α,p38β,p38γ,
p38δ) which retain a high sequence homology between
each other; p38αis 75% identical to p38βand shares
62% and 61% of identical protein sequence with p38γand
p38δ, respectively. In addition, p38γshares around 70% of
identical sequence with the p38δisoform. The four p38
MAPKs isoforms have been shown to be widely expressed
in different tissues and selectively initiate downstream
responses by activating a wide range of specifically selected
substrates [1,5,6]. Accordingly, the diversity in localisation
of p38 MAPK isoforms has been implicated in a wide range
of physiological processes (reviewed elsewhere [7]). The
proteins that compose the p38 MAPK signalling cascade were
also found to be highly expressed in mature neurons. More
exciting still was the fact that MAPKs, including the p38
MAPK cascade, were found to be stimulated by glutamate
receptor activation [8,9]. In the adult mouse brain the four
isoforms of p38 (α,β,γ,δ) have been shown to be expressed
in tissue from the whole brain, cerebellum, and cortex using
immunoblotting techniques [10]. p38αand p38βisoforms
Journal of Signal Transduction 3
were also reported to be localised in several regions of the
brain including the cerebral cortex and the hippocampus
in adult mouse brain tissue using immunohistochemistry
techniques [11]. Both p38αand p38βisoforms are diversely
distributed within cell types and cellular compartments.
Generally, throughout the brain, p38αis predominately
expressed in neuronal cells whereas p38βis highly expressed
in both neuronal and glial cells [11]. Diversity in isoform
expression is further observed with regards to the subcellular
localisation of p38αand p38βin CA1 hippocampal neurons,
with p38αbeing widely distributed throughout the neuronal
compartments including dendrites, cytoplasm and nucleus,
and p38βpreferentially localised in the nucleus [11]. The
MKK activators MKK3/6, and additionally MKK4, are all
expressed in the brain and are highly selective for the p38
MAPKs [5]. MKK6 has been shown to activate all p38 MAPK
isoforms and along with MKK3 are the main activators of
p38αwhich, together with p38β, are the most abundant
isoforms of p38 MAPK to be expressed in the brain [11].
Throughout this paper only the activation of p38αand p38β
isoforms will be discussed mainly due to the fact that the p38
MAPK inhibitors, SB203580 and SB202190, can specifically
block the activity of the p38αand p38βand do not inhibit
p38γand p38δisoforms [12] and also due to the fact that
only p38αand p38βisoforms can phosphorylate and activate
MK2.
Activation of p38 MAPK in microglia, astrocytes, and
neurons can all be induced through osmotic stress and the
release of cytokines such as tumour-necrosis-factor-
(TNF-)αand interleukin (IL) 1-α/β, which activate the
tumour necrosis factor receptor (TNFR) and interleukin-1
receptor (IL-1R), respectively. Interestingly, it has been
shown that cultured mice astrocytes stimulated with TNF-α
activated the p38 MAPK signalling cascade specifically
through the activation of TNFR-1 and not TNFR-2, which
is contrary to what has been shown in other cell types [13].
In rat cerebral microglial culture, it has been observed that
p38 MAPK activation, and the subsequent production of
cytokines, can be induced upon incubation with extracellular
heat-shock proteins (Hsps) Hsp90, Hsp70, and Hsp32 [14].
This discovery is appealing since Hsps have been associated
with a physiological protective mechanism in neurodegen-
erative diseases through regulating misfolded proteins and
protein aggregates, like that of tau in Alzheimer’s disease
(AD) and α-synuclein in Parkinson’s disease (PD). These
Hsps can act as chaperones to prevent aberrant interactions
between the misfolded protein aggregates and other cellular
proteins and assist in reducing the accumulation of toxic
oligomers in the cell by targeting the misfolded proteins
for degradation [15]. Since Hsps have also been shown to
induce microglial activation and downstream release of
cytokines, then it can be speculated that they are involved
in a neuroprotective mechanism or, if the glial cells become
overstimulated, cause neuroinflammation as a result of the
increase in release of inflammatory mediators. However
a considerable amount of research is needed to further
understand the precise role of Hsps in neurodegeneration.
Additionally, it has been demonstrated that Hsp activation
of the Toll-like receptor 4 (TLR4) pathway results in
phosphorylation of p38 MAPK as evidence shows that there
was a noticeable reduction in p38 MAPK phosphorylation
and suppression of microglial release of cytokines IL-6 and
TNF-αin the TLR4 mutant mouse [14].
3. Synaptic Plasticity and the Requirement of
the p38 MAPK Signalling Cascade
Exchange of information between neurons in the central ner-
vous system (CNS) occurs at synapses. Excitatory synapses
are composed of several specialised domains including the
presynaptic terminal that releases neurotransmitters and the
juxtaposed postsynaptic density containing a highly dense
agglomerate of proteins including (N-methyl-d-aspartate)
ionotropic glutamate receptors (NMDARs) and (α-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type gluta-
mate receptors (AMPARs). The activity in the postsynaptic
neuron is never a direct translation of the activity of
the presynaptic neuron as the synaptic strength of these
connections is constantly changing. This modulation in
activity at glutamatergic synapses is referred to as synap-
tic plasticity and can often persist over long periods of
time. These long-term processes are thought to be crucial
in initiating the cellular changes that underlie learning
and memory [16,17]. Long-term enhancement in the
strength of synaptic transmission is referred to as long-
term potentiation (LTP), whereas long-term decrease in
the strength of synaptic transmission is named long-term
depression (LTD). A well-characterised form of LTP requires
the activation of postsynaptic NMDARs which leads to
the influx of calcium through the NMDAR channel. The
influx of calcium initiates a cascade of events leading to the
insertion of AMPAR subunits into the postsynaptic density
and results in a rapid and sustained increase in synaptically
evoked excitatory postsynaptic potentials (EPSPs) [16,17].
Conversely, LTD involves either ionotropic receptors induced
through the activation of NMDARs (NMDAR-LTD) or
group I metabotropic glutamate receptors (GI-mGluR-LTD)
[18,19]. Activation of NMDAR or GI-mGluR triggers a
diversity of signalling cascades which results in a rapid
and sustained decrease in synaptically evoked EPSPs. LTP
and LTD are experimentally induced in the hippocampus
and over the last four decades the electrophysiological
properties as well as molecular mechanisms underlying
these processes have been extensively studied [16,17]. A
key step in elucidating the mechanisms underlying several
forms of synaptic plasticity was the discovery that AMPAR
subunits are rapidly trafficked in and out of the postsynaptic
density [16,18]. Four subunits of AMPAR, named GluA1-
4, are expressed in hippocampal neurons. GluA1-4 subunits
can associate in different combinations to form ion-gated
channels with diverse functional properties [16,17]. Con-
sequently, the major challenge facing scientists investigating
the regulation of AMPAR trafficking following induction
of synaptic plasticity is to map the proteins involved in
the cascade of events linking the activation of a specific
subclass of glutamate receptors such as NMDARs or GI-
mGluRs and the subsequent trafficking of AMPARs subunits.
4Journal of Signal Transduction
Naturally, this is a very daunting task as release of glutamate
at the synaptic shaft activates distinct postsynaptic receptors
and consequently several signalling pathways are stimulated
simultaneously (Figure 1(b)). However, with the develop-
ment of potent specific inhibitors for distinct kinase families
including MAPK signalling cascades, strong evidence has
emerged suggesting the requirement of MAPKs in synaptic
plasticity in the hippocampus [9,18,20–22].
Accordingly, the requirement of the p38 MAPK signalling
cascade in the induction of synaptic plasticity has been well
characterised [9,18] and there is a general consensus show-
ing that p38 MAPK is required in the induction of mGluR-
induced LTD [20,23] and NMDAR-induced LTD [18].
Several studies have characterised the molecular mechanism
involving the p38 MAPK cascade in GI-mGluR-dependent
LTD [20,23]. GI-mGluR-LTD involves the activation of Gq-
type G proteins which results in Gβγ release. The subsequent
activation of the small GTPase Rap 1 then activates MKKKs
and MKK3/6, which activate p38 MAPK (Figure 1(b)) [23].
Although it is known that mGluR-LTD is dependent on
the activation of p38 MAPK and that endocytosis governs
trafficking of the cell surface AMPA receptors GluA1 and
GluA2 subunits, the steps linking p38 MAPK activation to
the internalisation of GluA1 and GluA2 subunits are not
yet known. Furthermore, the direct targets downstream of
p38 MAPK underlying LTD have not yet been elucidated
(Figure 1(b)). A well-characterised target for p38 MAPK is
the MAPK-activated protein kinase (MKs) subfamily, which
structure, expression, and function will be discussed in the
next section. Interestingly, one important biological function
of the MKs is the regulation of the actin remodelling. As
p38 MAPK cascade plays an important role in the induction
of LTD and that an ever-increasing number of studies have
linked the trafficking of AMPA receptors underlying synaptic
plasticity to morphological changes in neuronal dendritic
spines [24], it is plausible to speculate that activation of p38
MAPK-MKs complex can potentially be involved in actin
remodelling at spines. Dendritic spines, where the majority
of the glutamatergic synapses occur, are small protrusions
in which stability is maintained in a dynamic fashion by the
actin cytoskeleton. The processes of actin polymerisation and
depolymerisation play a crucial role in the incredibly plastic
size and shape of dendritic spines of hippocampal neurons.
There is strong evidence to suggest that the shift in balance
between the amount of G-actin and F-actin in spines is
responsible for changes in the morphological characteristics
of the spines such as head volume, neck length, and number
of spines. Moreover, during LTP an increase in the number
and size of dendritic spines occurs in neuronal cells of the
hippocampus, whereas the opposite effect is observed when
LTD is induced [24].
3.1. p38 MAPK Substrates. Three key studies were published
in 1994 which provided the first step towards understanding
the functional role of the p38 MAPK signalling cascade in
mammalian cells. The identification of p38αMAPK (named
as p38 MAPK, [25]) activation residues together with the dis-
covery of MK2 as a direct substrate of p38 MAPK provided
the first insight into the molecular mechanism involved in
the activation of p38 MAPK cascades [26,27]. Since then
several other substrates of p38 MAPK have been identified
and characterized, for example, transcription factors that
are involved in cell development, cancer and myocyte
differentiation such as activating transcription factor 2 and
6 (ATF2/6), tumour suppressor protein p53, nuclear factor
of activated T cells (NFAT), and myocyte enhancer factors
(MEF2A and MEF2C), respectively. Furthermore, proteins
also involved in cell development, cancer and myocyte
differentiation such as Cdc25, C/EBP homologous protein
(CHOP), and kinases such as p38 activated/regulated protein
kinase (PRAK) and mitogen- and stress-activated kinase
(MSK1) have all be identified as p38 MAPK direct substrates
(For review see [1,28]). However, in this paper we want to
focus our attention on proteins that are activated only by p38
MAPK and on proteins that play a role in regulating neuronal
processes such as synaptic plasticity and neurodegenerative
disease.
Microtubule-associated protein tau, like MK2, has been
shown to be phosphorylated by p38 MAPK in neurons and is
therefore of interest in neuronal processes. In the following
sections we will describe the localisation, activation, and,
where possible, the physiological role of these two substrates
of p38 MAPK, MK2 and tau, and their role in actin remod-
elling. While the role of the p38 MAPK-MK2 cascade in actin
remodelling through posttranslational modifications has not
yet been studied in detail in neurons, a significant amount
of information is available on the molecular mechanism by
which p38 MAPK regulates neuronal tau function.
3.1.1. MAPKAP Kinases (MKs). MAPKAPK-2 (MK2) and
MAPKAPK-3 (MK3) are serine/threonine kinases belonging
to the MAPK-activated protein kinase subfamily that bind to
and are activated specifically by the p38α/βMAPK isoforms
[29,30]. MK2 is believed to be one of the most important
kinases to be activated by p38α/βMAPK due to its vital role
in mediating the cellular stress and inflammatory responses.
The MK2 enzyme is composed of a proline-rich N-
terminal domain, a catalytic domain, a C-terminal domain
containing an autoinhibitory A-helix (AH), the nuclear
export signal (NES), the nuclear localisation signal (NLS),
and the p38 MAPK-binding domain. Once activated, p38α/β
phosphorylate MK2 at Thr-222 located in the activation
loop, at Ser-272 located within the catalytic domain, and
at Thr-334, another regulatory phosphorylation site. One of
the most important characteristics of MK2 is the ability to
behave as a bifunctional switch, linking kinase activation to
its subcellular localisation. Upon phosphorylation at Thr-
334 by p38α/βMAPK, a conformational change occurs
within the MK2 structure allowing the exposure of the
masked NES as well as the exposure of the substrate-binding
site, permitting the translocation of the activated MK2 from
the nucleus to the cytoplasm of the cell. Contrary to the
regulated function of the NES, the NLS motif is active
independently of the phosphorylation state of MK2 there-
fore permitting the kinase to shuttle between nucleus and
cytoplasm [29,30]. Although both NES and NLS domains
are accessible in the kinase active state, it seems that the
nuclear export signal is more effective than the import signal.
Journal of Signal Transduction 5
Therefore, most of the shuttling of the active p38 MAPK-
MK2 is cytoplasmic, which directs the active p38 MAPK-
MK2 complex to be localised and to phosphorylate substrates
in the cytoplasm. Regarding the subcellular localisation of
MK2 in neurons, a significant increase in levels of MK2
mRNA has been reported in pyramidal cell layers of CA1 and
CA3 and in the granule cell layer of the dentate gyrus regions
of the hippocampus after kainic-acid-induced seizures [31].
Furthermore, high levels of endogenous MK2 protein are
also observed in the hippocampus and frontal cortex of
postnatal and adult mice using immunoblotting techniques
(SAL Corrˆ
ea, unpublished data).
Several proteins have been found to be phosphorylated
by MKs, which implicates the role of this enzyme in a wide
range of cellular functions [29]. These include interactions
with heat-shock proteins (Hsps) [32,33], the p16 sub-
unit (p16-Arc) of the seven-member actin-related protein-
2/3 complex (Arp2/3) [34], F-actin capping protein Z-
interacting protein (Cap-ZIP) [35], and lymphocyte-specific
protein (LSP)1 [36]. In 2011 an elegant study from Matthias
Gaestel’s laboratory showed that the p38 MAPK-MK2 com-
plex plays an important role in the activation of serum-
response-element- (SRE-) driven immediate early genes
(IEGs) by direct phosphorylation of serum response factors
(SRF) at Ser-103 [37]. These findings are very exciting as
transcriptional activation of Arc/Arg3.1 (activity-regulated
cytoskeleton-associated protein or activity-regulated gene
3.1), which is a neuron-specific IEG, has been shown to
be dependent on SRF activation in primary cortical neuron
culture [38,39]. Arc/Arg3.1 is thought to be a key regulator
of specific forms of synaptic plasticity that depend on protein
synthesis [39]. Accordingly, Arc/Arg3.1 has been shown to
regulate spine morphology [40], control trafficking of AMPA
receptors through its interaction with the endocytic machin-
ery [41], and is believed to regulate an endosomal pathway
involved in the generation of activity-dependent amyloid-
beta (Aβ)deposits[42]. However, the precise signalling
cascade(s) that modulates Arc/Arg3.1 function is far from
clear. All MK2 substrates described above are involved in
controlling actin remodelling, which suggests that the p38
MAPK-MK2/3 signalling cascade may play an important role
in the rearrangement of the actin cytoskeleton. Although
several other substrates for MKs have been characterised
[29], in this paper we will focus on the MK2 substrates
that potentially play a physiological role in controlling
actin dynamics in neurons and a pathophysiological role in
neuroinflammation and stress responses.
3.1.2. Tau. Tau is a highly soluble microtubule-associated
protein (MAP) in which subcellular localisation is deter-
mined by its phosphorylation status in neuronal cells. The
principal function of tau is to bind and stabilise cytoskeleton
microtubules (MTs) and thus tau protein is characterised
by the presence of a microtubule-binding domain. This
domain is comprised of multiple, highly conserved repeats of
a tubulin-binding motif and it is the number of these repeats
which defines the identity of each of the tau isoforms. Tau can
bind to microtubules through the globular protein tubulin,
which is the basic unit of microtubules. The tubulin-binding
repeats within the MT-binding domain bind to specific
regions of β-tubulin which are located on the microtubule
inner surface. Additionally, the positively charged proline
rich region, which is situated before the MT-binding domain,
can tightly bind to the negatively charged microtubule
surface [43]. These interactions therefore contribute to the
stabilisation of microtubules. The ability and binding affinity
of tau to interact with microtubules is regulated through
post-translational modifications, mainly through phospho-
rylation of serine and threonine residues. This regulatory
phosphorylation is tightly controlled by numerous protein
phosphatases and kinases, and consequently p38 MAPK
has been identified as one of the kinases involved in tau
regulation [44,45].
p38 MAPK can directly phosphorylate tau protein in
vitro and in vivo. There are 85 putative phosphorylation
sites situated on tau of which 79 are either serine (45)
or threonine residues (34) [44,46,47]. Of these, p38
MAPK has been shown to phosphorylate Ser-46, Thr-
181, Ser-202, Thr-205, Thr-212, Thr-217, Thr-231, Ser-235,
Ser-356, Ser-396 and Ser-404 [44]. Tau has been shown
to be predominately localised to the axonal regions of
nonstimulated neurons [48]. However, when the proline-
rich region of tau is hyperphosphorylated, tau is seen to be
localised in the somatodendritic compartments of neurons
[49–52]. Therefore, the phosphorylation status of tau is of
crucial importance in determining its binding partners and
consequently its functional role as a result of its differential
localisation. The phosphorylation of a particular residue Ser-
356 has been proposed to instigate detachment of tau from
the microtubules [44,47,53], and since this residue has
been shown to be phosphorylated by p38 MAPK then p38
MAPK could potentially be involved in the destabilisation of
the microtubules. Additionally, phosphorylation of residues
Thr-231 and Ser-235 by p38 MAPK has also been shown to
contribute to tau detachment from microtubules [54]. This
physiological role of p38 MAPK in tau phosphorylation can
turn into a pathophysiological role if tau becomes hyper-
phosphorylated. Since this hyperphosphorylation results in
increased tau detachment from microtubules, then there is
an increase in the amount of soluble tau present in the
neuron, which is therefore prone to self-aggregation and
polymerisation, leading to the formation of tau oligomers.
These oligomers combine and further aggregate to form
paired helical filaments (PHFs) which then assemble to form
neurofibrillary tangles (NFTs) as seen within diseases such as
Alzheimer’s disease.
3.2. p38 MAPK in Neurodegenerative Diseases. Dysfunction
within neuronal signalling pathways led to neurodegenera-
tive diseases and the p38 MAPK signalling pathway is no
exception. Irregularities in p38 MAPK signalling in neuronal
cells have been linked with neuroinflammatory processes and
with diseases such as Alzheimer’s disease, Parkinson’s disease,
amyotrophic lateral sclerosis (ALS), and Pick’s Disease (PiD).
3.2.1. Neuroinflammation. Theprocessofacuteinflamma-
tion in mammalian tissue is one of extreme importance
6Journal of Signal Transduction
SB 203580
BIRB0796 p38 α/β
MAPKAP kinase 2
Release of TNF-α, IL-α,
IL-1β, IL-6
Neuroinflammation
Neurofibrillary tangles
Parkinson’s disease
p16-Arc, Hsp25/27
Remodelling of actin
Spine morphology
Alzheimer’s disease Pick’s diseaseAlzheimer’s disease
Tau hyperphosphorylation
Mislocation of tau
Tau protein
TTP, ARE-binding proteins
Transcription of cytokines
SRF
Transcription
of Arc/Arg 3.1
(a) (b)
Figure 2: Schematic drawing illustrating the steps linking the p38 MAPK substrates to neurodegenerative disease. (a) The p38 MAPK-MK2
complex plays a role in neuroinflammation by phosphorylating AU-rich-element- (ARE-) binding proteins, such as tristetraprolin (TTP),
which consequently can bind directly or indirectly to ARE sites present in TNF and other cytokine genes leading to transcription, translation,
and subsequent release of mediators causing inflammation. The p38 MAPK-MK2 axis potentially plays an important role controlling
dendritic spine morphology via direct activation of p16-Arc and Hsp, which are proteins involved in actin remodelling. Activity-dependent
induction of p38 MAPK-MK2 axis can play an important role in the expression of the immediate early gene Arc/Arg3.1 which regulates
spine morphology in neurons via activation of serum-response-factor- (SRF-) serum response element (SRE) complex. p38 MAPK-MK2
signalling cascade activation can have an effect on morphological changes observed at dendritic spines, a pattern that is observed during
the development of neurodegenerative disease. (b) p38 MAPK phosphorylates tau protein at several residues. Hyperphosphorylated tau,
contributes to the formation of tau oligomers. The aggregation of the tau oligomers forms the paired-helical filaments (PHFs), which then
assemble together to form neurofibrillary tangles that are characteristically observed in the brain of patients suffering from Alzheimer’s
disease.
as it is the immediate cellular response to injury and is a
defensive mechanism to prevent damage to the cell. Chronic
inflammation occurs when there are persistent inflammatory
stimuli that can have a damaging rather than protective
effect. For example, chronic glial cell activation is seen to be
increased in neurodegenerative disease [55], which will be
discussed in the following section.
One of the many physiological roles of glial cells within
the brain, such as astrocytes and microglia, is to protect the
brain from stress and other cellular stimuli and to act as
mediators in inflammation and neuroprotection. Prolonged
and sustained activation of glial cells can result in an exagger-
ated inflammatory response and as a result cause neuronal
cell death through the elevated release of proinflammatory
cytokines, which have a potential neurotoxic effect, leading
to increased neurodegeneration [56,57]. The majority of
studies investigating the role of p38 MAPK in mammalian
cells focus on its function in the process of inflammation.
It is known that p38 MAPK becomes stimulated in re-
sponse to extracellular stimuli such as stress factors and
cytokines [58,59](Figure 1(a)). Exposures of cells to stress
factors/cytokines stimuli activate a number of MKKKs,
for example, TGF-beta-activated kinase 1 (TAK 1) and
apoptosis signal-regulated kinase 1 (ASK-1) (Figure 1(a)).
The function of these kinases is to phosphorylate the down-
stream kinases MKK3/6, which are the known activators
of p38α/β MAPK. Many p38 MAPK targets are kinases
and transcription factors which are known to play a role
in inflammation through the production and activation of
inflammatory mediators. The p38 MAPK-MK2 complex
is known to contribute to the inflammation process as
it has been observed in vivo that MK2 knockout mice
are resistant to endotoxic shock when stimulated with
lipopolysaccharide LPS (Figure 2(b)) [60]. It has also been
recognised that MK2 is involved in regulating the production
of TNF-α, interleukin-6 (IL-6), interleukin-8 (IL-8), and
other cytokines which all play a role in the process of
inflammation [61,62]. In addition it has been seen that
MK2 expression and activation is increased in LPS- and
interferon-γ-stimulated microglial cells, which can release
inflammatory mediators, and that microglial cells cultured
from MK2 knockout mice showed a decrease in the release of
inflammatory cytokines [63]. This signalling is of particular
interest as it has been documented that the p38 MAPK-MK2
Journal of Signal Transduction 7
pathway and the consequent production of inflammatory
cytokines have a significant role in neurodegenerative disease
with oxidative stress and persistent neuroinflammation being
the primary cause for such disease (Figure 2(a)).
3.2.2. Alzheimer’s Disease. Alzheimer’s disease is the most
common form of dementia and is becoming increasingly
prevalent with an estimation that 1 in 85 people globally will
be affected by 2050 [64]. The disease is typically characterised
by the presence of Aβplaques or NFTs formed from free
aggregated neuronal tau within the brain. However the
relationship between these structures and the symptoms of
cognitive impairment and memory loss that is associated
with the disease remains uncertain. Increasing evidence
has shown that the stability of dendritic spines and actin
remodelling may participate in the pathology of the disease.
The loss of synapses is a common occurrence within
postmortem tissue of AD patients [65]. Many studies and
findings in animal models have linked early symptoms of AD
with loss in cognition, combined with a reduced number of
dendritic spines in the hippocampus [66,67], which is one of
the most affected areas of the brain in this disease. It has been
shown that dendritic spines become increasing destabilised,
have aberrant morphology, and are subject to degeneration
as a consequence of the accumulation of toxic Aβoligomers
[68] and their direct binding with the spine head [69,
70]. The direct Aβ-oligomer-binding site is not yet known;
however evidence shows these oligomers act as specific
ligands to bind to or near targets on the spine surface and
it has been observed that these oligomers bind to neurons
from mature hippocampal cultures expressing the NMDA
receptor subunits, GluN1 and GluN2B but not astrocytes
and inhibitory neurons [69,70]. Furthermore, analysis of
postmortem tissue collected from AD patients has shown
an increase in the amount of p38 MAPK phosphorylation
associated with Aβplaques and NFTs [71] and that mutant
tau (P301L) becomes mislocated to the somatodendritic
compartments of the neuron compared to healthy neurons
where tau is expressed principally throughout the axon [45,
48].
Although the predominant function of tau protein is to
assist in the stabilisation of microtubules through its binding
to β-tubulin, it possesses additional regulatory functions.
Recent interesting findings have shown that there is a sig-
nificant increase in the binding affinity between hyperphos-
phorylated tau and F-actin in vivo. Experiments using brains
of transgenic Drosophila melanogaster expressing wild-type
human tau or a hyperphosphorylated mutant (R406W)
form clearly demonstrated that the amount of F-actin
immunoprecipitated with hyperphosphorylated tau mutant
is significantly higher when compared with the amount of F-
actin immunoprecipitated with wild-type tau [72–74]. Little
information is available about the interaction sites between
tau and actin. However it is known that the microtubule-
binding domain (MTBD) is primarily involved with this
association [75,76]. Furthermore, it has been shown that the
proline-rich domain of tau protein is important in assisting
the actin-tau interaction as this domain alone is able to bind
toF-actinandcanevenpromoteF-actinbundling[77].
Elucidating the precise molecular mechanism underlying
the rearrangement of the actin cytoskeleton in spines is
extremely important. Potentially, the physiological role of
the p38 MAPK signalling cascade could be involved in the
rearrangement of the actin cytoskeleton in dendritic spines
through different targets. Activity-dependent induction of
the p38 MAPK-MK2 axis leading to the phosphorylation
of SRF in neurons can potentially trigger the activation
of Arc/Arg3.1 transcription (Figure 2(a)). Given the impor-
tance of Arc/Arg3.1 protein in the molecular mechanism
underlying synaptic plasticity, in regulating spine morphol-
ogy and in promoting the stability of the actin network, the
knowledge of the precise signalling cascade(s) controlling
Arc/Arg 3.1 transcription could provide insightful infor-
mation on the function of this multitalented protein and
its function in neurodegenerative disease [39–42]. Activated
p38 MAPK-MK2 axis could also potentially regulate Arp2/3
complex through phosphorylation of actin remodelling
proteins such as p16-Arc in neurons (Figure 2(a)). p16-Arc
has been shown to interact with and is phosphorylated by
MK2 at Ser-77 in vitro [34]. Strong evidence suggests that the
Arp2/3 complex is required for changes in dendritic spine
morphology as it plays a key role in the formation of
branched actin filamentous networks [78–80]. Another po-
tentially important role for p38 MAPK signalling pathway in
actin remodelling in neurons is via tau. p38 MAPK-depend-
ent hyperphosphorylation of tau could induce tau misloca-
tion from the axon to dendritic spines, where hyperphos-
phorylated tau is then able to bind to F-actin (Figure 2(b))
[72]. However further experimental work in neurons is
needed not only to validate the p38 MAPK downstream
substrates, but also to show their functional importance
in remodelling dendritic spines in healthy neurons and in
neurodegenerative diseases.
In addition to the aforementioned association with
plaques and tangles, p38 MAPK is involved with the inflam-
matory response. It was shown that Aβis able to stimulate
glial cell cultures and activate p38 MAPK [81]andMK2,thus
upregulating the production of inflammatory cytokines such
as IL-1βand TNF-αin hippocampal extracts (Figure 2(b))
[82,83]. It is this increased release of inflammatory medi-
ators from overstimulation of Aβ-stimulated glial cells that
can cause a neuroinflammatory and neurotoxic effect on sur-
rounding neurons [84], contributing to the loss of neurons
witnessed in neurodegenerative disease. Aβhas also been
shown to stimulate microglia in vivo, where direct injection
of Aβinto rat striatum resulted in the activation of microglia,
the production of cytokines, and eventually loss of neuronal
cells [85]. In AD, it has been shown that microglia accu-
mulate at the site of Aβdeposition and actively clear such
deposits [86] through their phagocytic abilities. Microglia
also produce a neuroprotective inflammatory response from
activation of toll-like receptors (TLRs) which can induce
the production of inflammatory mediators through the
MKK6-p38 MAPK-MK2 cascade, as described previously
(Figures 1(a) and 2(b)). If glial overactivation occurs through
Aβplaque stimulation, then this inflammatory response can
lead to neuronal cell death as observed in rat brain in vivo
[87]. Upon the application of the novel and selective p38α
8Journal of Signal Transduction
MAPK inhibitor MW01-2-069A-SRM (069A), this increase
in the production of inflammatory molecules from glial cells
is blocked [82] hence highlighting the importance of p38
MAPK as a target to combat neuroinflammation and the
pathological consequences that arise as a result.
Glial-neuron interactions and the effect these interac-
tions have on tau phosphorylation have been analysed in
vitro. It has been demonstrated that release of proinflam-
matory cytokine IL-1 from activated microglia increased the
levels of tau phosphorylation in neurons. These changes
are partly mediated through activation of p38 MAPK as a
significant increase in the levels of phospho-p38 MAPK was
observed upon application of IL-1βin cultures of neocortical
neurons and microglia [88]. Additionally, upon inhibition of
p38 MAPK with SB203580, it was observed in vitro that IL-
1β-induced tau phosphorylation was considerably decreased
in neuronal culture [88], again highlighting the importance
of p38 MAPK in cytokine release and tau phosphorylation,
linking chronic glial cell activation and interactions with
neurons with tau pathology in neurodegenerative disease.
Under pathophysiological conditions, activated p38αhas
been seen to localise to areas where NFTs, amyloid plaques,
and glial cells are present both within human AD brain
and transgenic mouse models [71,89,90]. Furthermore, an
increase in the activation and expression levels of one of the
upstream activators of p38 MAPK, MKK6, has been observed
in AD brain tissue [91] and to be colocalised with activated
p38 MAPK in areas containing NFTs and plaques. Addition-
ally, ASK-1, a specific activator of MKK6, has been shown
to form an active complex with amyloid precursor protein
(APP) [92], the precursor to Aβ. This complex, which
forms through Aβ-peptide-induced dimerisation, suggests
a connection between the aberrant processing of APP and
the ASK-1-MKK6-p38 MAPK cascade which is involved
in inflammation and abnormal tau phosphorylation [93].
In vitro activation of MKK6-p38 MAPK has led to tau
phosphorylation at specific sites, the most efficient being Ser-
396, which has been suggested to have a functional role in
microtubule binding. Abnormal phosphorylation at Ser-396
is observed in AD brain but not in normal functioning adult
brain [94]. Furthermore, it has been seen in AD hippocampal
extracts taken from post-mortem human brain that MKK6
can coimmunopreciptate with phosphorylated tau protein
and that APP is also able to coimmunoprecipitate with both
ASK-1 and MKK6 [93]. This suggests that APP, once stimu-
lated by Aβpeptide, can activate the upstream MKKK ASK-1
and MKK6, consequently activating p38 MAPK, which can
directly phosphorylate tau protein hence linking deposition
of Aβplaques to downstream tau phosphorylation through
the activation of the p38 MAPK signalling cascade under
pathophysiological conditions.
Pick’s disease is another severe neurodegenerative dis-
order, which involves progressive dementia and aphasia
through the development of Pick bodies, which are com-
prised of neurofibrils formed of aggregated phosphorylated
tau. It is known that oxidative stress is involved in instigating
Pick’s disease, and since it has been highlighted that the
p38 MAPK cascade is activated upon such stimuli, it may
play an important role in this disease as well. It has been
observed in post-mortem brain tissue that phosphorylated
p38 MAPK localises to the Pick bodies which contain highly
phosphorylated tau protein, and since p38 MAPK is capable
of phosphorylating tau, as described above, it emphasises the
importance of p38 MAPK in this disease as well as AD and
other related tauopathies [95].
3.2.3. Parkinson’s Disease. Parkinson’s disease is the sec-
ond most prevalent neurodegenerative disease and around
127,000 people in the UK are currently living with the
disease, which has been estimated to rise by 28% by the year
2020 [96]. PD involves the substantial loss of dopaminergic
neurons from the substantia nigra and the accumulation
of aggregated protein deposits, which form cytoplasmic
inclusions called Lewy bodies (LBs). The aggregation of
these protein dense structures subsequently causes defects in
the central nervous system and severely impairs motor and
cognitive abilities [97]. Mutations within 9 genes (SNCA,
UCHL1, LRRK2, GIGYF2, HtrA2, PRKN, PINK1, DJ-1, and
ATP13A2) [98] have been discovered and linked to PD. An
important gene encodes α-synuclein (SNCA), which is a
protein present within the LBs of PD patients and known
to play a pivotal role in the development of the disease.
α-Synuclein is highly expressed in neuronal tissue and is
subject to many post-translational modifications such as
phosphorylation and ubiquitination, although its physiolog-
ical function is poorly characterised. It has been suggested,
however, that these post-translational modifications partic-
ipate in neurotoxicity [99]asaggregatedα-synuclein is the
predominant fibrillar component of the proteinaceous Lewy
bodies seen in PD. Additionally, it has been observed that
amplified α-synuclein levels are linked to an increase in
neuroinflammation as it has been shown that α-synuclein
activates p38 MAPK and other MAPKs in glial cells, a
finding that is supported by the fact that extracellular α-
synuclein released from damaged neurons interacts with
microglia [100]. As described above, the activation of glial
cells through the p38 MAPK-MK2 cascade consequently
results in the production of inflammatory cytokines and
TNF-α, which can induce and promote neuroinflammation
as a physiological neuroprotective mechanism. If the glial
cells become overactivated, however, as may occur through
elevated levels of extracellular α-synuclein released from
damaged Lewy body containing neurons, then chronic
inflammation could be established and lead to neuronal cell
death.
MAPKAP kinase-2, one of p38 MAPK more prevalent
substrates has also been implicated within PD, where it
has been shown that MK2-deficient mice show decreased
levels of neuroinflammation and loss of dopaminergic
neurons within the substantia nigra after treatment with
the Parkinson’s inducing neurotoxin MPTP compared to
MK2 wild-type mice [101]. MK2, after activation by p38
MAPK, is known to induce the transcription and release
of proinflammatory molecules such as IL-1, IL-6, and
TNF-α, thus causing neuroinflammation and potentially
neuronal cell death. An investigation by Culbert et al. [63]
demonstrates that if MK2 is eliminated in microglia then
this neurotoxic inflammatory mechanism is reduced as the
Journal of Signal Transduction 9
release of proinflammatory mediators is inhibited, resulting
in mice that exhibit a neuroprotective phenotype therefore
preventing neuronal cell death.
4. Concluding Remarks
Considerable progress has been made in the understanding
of the functional role of the p38 MAPK signalling cascade in
synaptic plasticity in the hippocampus and its potential role
in neurodegenerative diseases such as AD. However, less is
known regarding the role of the direct targets of p38 MAPK,
such as MK2 and tau, in regulating neuroinflammation
and the actin cytoskeleton in dendritic spines of neuronal
cells. Growing evidence suggests that remodelling of actin at
dendritic spines plays a crucial role in synaptic plasticity and
therefore in cognitive processes such as learning and mem-
ory. Furthermore, recent findings in animal models have
linked early symptoms of AD with loss of cognitive functions,
combined with a reduced number of dendritic spines in the
hippocampus. Abnormal dendritic spine morphology has
also been observed in brain tissue from patients suffering
from AD. Therefore, with an ageing population continuing to
grow and the consequent rise in AD, elucidating the precise
role of p38 MAPK-MK2 and p38 MAPK-tau signalling
cascades in controlling actin remodelling becomes very
important as it may identify novel targets to slow down the
cognitive decline observed in normal ageing and in the early
stages of neurodegenerative diseases.
Acknowledgments
TheauthorsaregratefultoDrs.J
¨
urgen M¨
uller and Daniel
Fulton for their helpful comments on the paper. S. A. L.
Corrˆ
ea is a Warwick Research Fellow and K. L. Eales is a
Research Assistant funded by the BBSRC. Work in SAL
Corrˆ
ea laboratory is supported by the BBSRC (BB/H018344/
1 and BB/J02127X/1) and Research Development Fund-
University of Warwick.
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