Modulation of GSK-3 as a Therapeutic Strategy on Tau Pathologies

Abstract

Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed and unusually active in resting, non-stimulated cells. In mammals, at least three proteins (α, β1, and β2), generated from two different genes, gsk-3α and gsk-3β, are widely expressed at both the RNA and protein levels although some tissues show preferential expression of some of the three proteins. Control of GSK-3 activity occurs by complex mechanisms that depend on specific signaling pathways, often controlling the inhibition of the kinase activity. GSK-3 appears to integrate different signaling pathways from a wide selection of cellular stimuli. The unique position of GSK-3 in modulating the function of a diverse series of proteins and its association with a wide variety of human disorders has attracted significant attention as a therapeutic target and as a means to understand the molecular basis of brain disorders. Different neurodegenerative diseases including frontotemporal dementia, progressive supranuclear palsy, and Alzheimer’s disease, present prominent tau pathology such as tau hyperphosphorylation and aggregation and are collectively referred to as tauopathies. GSK-3 has also been associated to different neuropsychiatric disorders, like schizophrenia and bipolar disorder. GSK-3β is the major kinase to phosphorylate tau both in vitro and in vivo and has been proposed as a target for therapeutic intervention. The first therapeutic strategy to modulate GSK-3 activity was the direct inhibition of its kinase activity. This review will focus on the signaling pathways involved in the control of GSK-3 activity and its pathological deregulation. We will highlight different alternatives of GSK-3 modulation including the direct pharmacological inhibition as compared to the modulation by upstream regulators.

Glycogen synthase kinase-3: cryoprotection and glycogen metabolism in the freeze-tolerant wood frog

“…When GSK-3 is phosphorylated and inactivated, GS can be dephosphorylated and activated, allowing glycogenesis to occur. In addition to its role in glycogen metabolism, GSK-3 has been shown to be a master kinase and is recognized to have roles in: (i) the Wnt signalling pathway, known to regulate several physiological processes as well as development, embryogenesis and cancer (Ding and Dale, 2002); (ii) protein synthesis (Welsh and Proud, 1993); (iii) the response to DNA damage (Watcharasit et al, 2002); (iv) the immune response (Beals et al, 1997); and (v) regulation of Tau protein in neurodegenerative disease (Medina et al, 2011), among others.…”

Neurological Functions of the Masterswitch Protein Kinase – GSK-3

“…The first indication of an important brain function was made in 1992 by Hanger et al (1992) who showed that GSK-3 phosphorylates the microtubule-associated protein tau at sites relevant to the pathology of Alzheimer's disease, further supported by studies by Takahashi et al (1994) who demonstrated that Tau was indeed a physiological substrate of GSK-3, which at that time was also called tau protein kinase I (TPKI) (reviewed in Kremer et al, 2011;Medina et al, 2011;Takashima, 2012). These findings were important milestones for initiating interest in GSK-3 in the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (see Gomez-Sintes et al, 2011;Kremer et al, 2011;Medina et al, 2011;Takashima, 2012).…”

PCDH10 inhibits cell proliferation of multiple myeloma via the negative regulation of the Wnt/β-catenin/BCL-9 signaling pathway

“…PCDH10 effectively obstructed the protein expression of AKT. Furthermore, it has been shown that the activation of AKT promotes the phosphorylation of GSK3β and accelerates the development of various types of cancer (33,34). This allows PCDH10 to upregulate GSK3β by blocking the activity of AKT, which in turn, stimulates the phosphorylation of β-catenin but decreases the protein expression of β-catenin in the cytoplasm and nucleus.…”

“…Since the expression of GSK3β is promoted by the re-expression of PCDH10, PCDH10 is more involved in intracellular signaling then adhesion ability (5) and GSK3β is frequently downregulated by the activity of PI3K/AKT (33,34). Thus, we hypothesized that PCDH10 increased the expression of GSK3β by obstructing the activity of AKT.…”