Glycogen synthase kinase-3 beta (GSK-3β) signaling: Implications for Parkinson's disease

Glycogen synthase kinase 3 (GSK-3) dysregulation plays an important role in the pathogenesis of numerous disorders, affecting the central nervous system (CNS) encompassing both neuroinflammation and neurodegenerative diseases. Several lines of evidence have illustrated a key role of the GSK-3 and its cellular and molecular signaling cascades in the control of neuroinflammation. Glycogen synthase kinase 3 beta (GSK-3 beta), one of the GSK-3 isomers, plays a major role in neuronal apoptosis and its inhibition decreases expression of alpha-Synuclein (alpha-Synuclein), which make this kinase an attractive therapeutic target for neurodegenerative disorders. Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. Thus, understanding the role of GSK-3 beta in PD will enhance our knowledge of the basic mechanisms underlying the pathogenesis of this disorder and facilitate the identification of new therapeutic avenues. In recent years, GSK-3 beta has been shown to play essential roles in modulating a variety of cellular functions, which have prompted efforts to develop GSK-3 beta inhibitors as therapeutics. In this review, we summarize GSK-3 signaling pathways and its association with neuroinflammation. Moreover, we highlight the interaction between GSK-3 beta and several cellular processes involved in the pathogenesis of PD, including the accumulation of alpha-Synuclein aggregates, oxidative stress and mitochondrial dysfunction. Finally, we discuss about GSK-3 beta inhibitors as a potential therapeutic strategy in PD. (C) 2015 Published by Elsevier Ltd.