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.
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, differentiation, 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 [
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 isoforms have been shown to be highly expressed in the brain, only a handful of brain-specific substrates for p38 MAPK have been characterised
The cascade of events leading to p38 MAPK activation is highly conserved throughout mammalian tissues including neuronal cells (Figures
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.
Mammalian cells are known to express four different genes encoding p38 MAPK isoforms (p38
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-)
Exchange of information between neurons in the central nervous 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 (
Accordingly, the requirement of the p38 MAPK signalling cascade in the induction of synaptic plasticity has been well characterised [
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 p38
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 remodelling. 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.
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 p38
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, p38
Several proteins have been found to be phosphorylated by MKs, which implicates the role of this enzyme in a wide range of cellular functions [
Tau is a highly soluble microtubule-associated protein (MAP) in which subcellular localisation is determined 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
p38 MAPK can directly phosphorylate tau protein
Dysfunction within neuronal signalling pathways led to neurodegenerative 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).
The process of acute inflammation in mammalian tissue is one of extreme importance 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 [
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 exaggerated 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 [
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.
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 [
Although the predominant function of tau protein is to assist in the stabilisation of microtubules through its binding to
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
In addition to the aforementioned association with plaques and tangles, p38 MAPK is involved with the inflammatory response. It was shown that A
Glial-neuron interactions and the effect these interactions have on tau phosphorylation have been analysed
Under pathophysiological conditions, activated p38
Pick’s disease is another severe neurodegenerative disorder, which involves progressive dementia and aphasia through the development of Pick bodies, which are comprised 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 [
Parkinson’s disease is the second 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 [
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 [
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 memory. 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.
The authors are grateful to Drs. Jürgen Müller and Daniel Fulton for their helpful comments on the paper. S. A. L. Corrêa is a Warwick Research Fellow and K. L. Eales is a Research Assistant funded by the BBSRC. Work in SAL Corrêa laboratory is supported by the BBSRC (BB/H018344/1 and BB/J02127X/1) and Research Development Fund-University of Warwick.