p38 MAPK and PI3K/AKT Signalling Cascades inParkinson's Disease

Abstract

Parkinson's disease (PD) is a chronic neurodegenerative condition which has the second largest incidence rate among all other neurodegenerative disorders barring Alzheimer's disease (AD). Currently there is no cure and researchers continue to probe the therapeutic prospect in cell cultures and animal models of PD. Out of the several factors contributing to PD prognosis, the role of p38 MAPK (Mitogen activated protein-kinase) and PI3K/AKT signalling module in PD brains is crucial because the impaired balance between the pro- apoptotic and anti-apoptotic pathways trigger unwanted phenotypes such as microglia activation, neuroinflammation, oxidative stress and apoptosis. These factors continue challenging the brain homeostasis in initial stages thereby essentially assisting the dopaminergic (DA) neurons towards progressive degeneration in PD. Neurotherapeutics against PD shall then be targeted against the misregulated accomplices of the p38 and PI3K/AKT cascades. In this review, we have outlined many such established mechanisms involving the p38 MAPK and PI3K/AKT pathways which can offer therapeutic windows for the rectification of aberrant DA neuronal dynamics in PD brains.

Keywords: PI3K/AKT; Parkinson’s disease (PD); apoptosis; neuroinflammation; neurotherapeutics; oxidative stress (OS); p38MAPK.

Fig. 1

p38 MAPK interactions involved in Parkinson’s disease neuropathology and associated neurodegeneration. Neurotoxins viz. rotenone, maneb, paraquat and MPTP evokes numerous detrimental phenotypes in degenerating neurons and p38 MAPK is responsible for microglia activation, induction of oxidative stress, apoptosis, neuroinflammation and neurodegeneration as triggered by these toxins

Fig. 2

Neuroprotective cross-talk involving the cytoprotective PI3K/AKT pathway. AKT when optimally activated by phosphorylation at serine and threonine residues, can interact with a spectrum of molecules to erect an anti- inflammatory (DJ-1 and HIF-1α) and anti- apoptotic (Bcl-2) ambience in vulnerable neurons. In addition, phosphorylated AKT can also promote autophagy via PINK-1 and Parkin. IRS-1 activation takes place via IGF-1/AKT cascade and other AKT targets including p85β and SPRED 1 are known to be downregulated by miR-126 in PD neurons. Activation (green arrows); prevention or suppression (red arrows