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

Sônia A L Corrêa,Katherine L Eales

doi:10.1155/2012/649079

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.

Highlights

The mitogen-activated protein kinase (MAPK) 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
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
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 Alzheimer’s disease (AD)

Summary

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, differentiation, and cell survival in mammalian cells. P38α and p38β isoforms were 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 p38α and p38β isoforms are diversely distributed within cell types and cellular compartments. 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) Hsp, Hsp, and Hsp32 [14] This discovery is appealing since Hsps have been associated with a physiological protective mechanism in neurodegenerative 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). 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-α in the TLR4 mutant mouse [14]

Synaptic Plasticity and the Requirement of the p38 MAPK Signalling Cascade

Findings

Concluding Remarks