The Role of p38 MAPK and Its Substrates in Neuronal Plasticity and Neurodegenerative Disease

Abstract

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.

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.

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.