Role of Mitogen Activated Protein Kinase Signaling in Parkinson's Disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder caused by insufficient dopamine production due to the loss of 50% to 70% of dopaminergic neurons. A shortage of dopamine, which is predominantly produced by the dopaminergic neurons within the substantia nigra, causes clinical symptoms such as reduction of muscle mass, impaired body balance, akinesia, bradykinesia, tremors, postural instability, etc. Lastly, this can lead to a total loss of physical movement and death. Since no cure for PD has been developed up to now, researchers using cell cultures and animal models focus their work on searching for potential therapeutic targets in order to develop effective treatments. In recent years, genetic studies have prominently advocated for the role of improper protein phosphorylation caused by a dysfunction in kinases and/or phosphatases as an important player in progression and pathogenesis of PD. Thus, in this review, we focus on the role of selected MAP kinases such as JNKs, ERK1/2, and p38 MAP kinases in PD pathology.

Keywords: ERK1/2; JNKs; Parkinson’s disease; apoptosis; mitochondrial dysfunction; neuro-inflammation; neurodegeneration; oxidative stress; p38 MAPKs.

Figure 1

Principal pathological processes in PD etiology and clinical hallmarks of the disease. SNpc—substantia nigra pars compacta, VTA—ventral tegmental area.

Figure 2

Involvement of MAPKs in processes that lead to Parkinson’s disease pathology. Different stimuli (stress stimuli, growth factors, cytokines, mitogens, pathogens, toxins) induce activation of MAPK pathways including activation of MAPKKK and MAPKK followed by phosphorylation of downstream targets such as JNKs, p38 MAPKs, and ERK1/2. JNKs and p38 MAPKs are grouped together due to their involvement in the “death pathway” (marked in red) while ERK1/2 is believed to promote cell growth and differentiation (marked in green). Activation of JNKs and p38 MAPKs promote oxidative stress and apoptosis, which are main contributors to PD pathogenesis. Oxidative stress may also cause microglial activation and chronic inflammation, which are toxic for brain cells and leads to PD pathology. In addition, ERK1/2 contribute to apoptosis of brain cells through the activation of NFAT and p53 and to neuronal inflammation through the activation of STATs. Both ERK1/2 and JNKs activate mTOR signaling, which promotes neurodegeneration such as that observed in PD.