GSK3α: An Important Paralog in Neurodegenerative Disorders and Cancer

Abstract

The biological activity of the enzyme glycogen synthase kinase-3 (GSK3) is fulfilled by two paralogs named GSK3α and GSK3β, which possess both redundancy and specific functions. The upregulated activity of these proteins is linked to the development of disorders such as neurodegenerative disorders (ND) and cancer. Although various chemical inhibitors of these enzymes restore the brain functions in models of ND such as Alzheimer’s disease (AD), and reduce the proliferation and survival of cancer cells, the particular contribution of each paralog to these effects remains unclear as these molecules downregulate the activity of both paralogs with a similar efficacy. Moreover, given that GSK3 paralogs phosphorylate more than 100 substrates, the simultaneous inhibition of both enzymes has detrimental effects during long-term inhibition. Although the GSK3β kinase function has usually been taken as the global GSK3 activity, in the last few years, a growing interest in the study of GSK3α has emerged because several studies have recognized it as the main GSK3 paralog involved in a variety of diseases. This review summarizes the current biological evidence on the role of GSK3α in AD and various types of cancer. We also provide a discussion on some strategies that may lead to the design of the paralog-specific inhibition of GSK3α.

Targets and mechanisms of Alpinia oxyphylla Miquel fruits in treating neurodegenerative dementia

“…Pinocembrin, which is a flavonoid, exerts neuroprotective effects through the GSK3β and Akt signaling pathways ( Kim et al, 2020 ). In neurodegenerative diseases such as AD, the activation of GSK3α not only participates in the process of APP hydrolysis to form Aβ but also regulates the phosphorylation of tau ( Silva-Garcia et al, 2020 ). Moreover, GSK3α is important in the regulation of synaptic plasticity.…”

Specific Role for GSK3α in Limiting Long-Term Potentiation in CA1 Pyramidal Neurons of Adult Mouse Hippocampus

“…Dysregulation of GSK3 is implicated in many major diseases, including cancer, inflammation, diabetes, cardiac hypertrophy and an array of CNS disorders (see reviews by Beurel et al, 2015;Ahmad and Woodgett, 2020;Hajka et al, 2021). In terms of brain disorders, GSK3 has been strongly implicated in, for example, sleep disorder, psychiatric illness, neurodevelopmental disorders including autism, intellectual disability, epilepsy and neurodegenerative disorders, in particular Alzheimer's disease (see reviews by Jaworski et al, 2019;Jaworski, 2020;Silva-García et al, 2020;Rizk et al, 2021;Sayas and Ávila, 2021). Investigating the roles of GSK3 is therefore central to the understanding of how its dysregulation may contribute to a wide array of serious conditions.…”

Thiazolo[5,4‐f]quinoxalines, Oxazolo[5,4‐f]quinoxalines and Pyrazino[b,e]isatins: Synthesis from 6‐Aminoquinoxalines and Properties

“…While a few thiazolo [5,4-f]quinoxalines have been claimed in patents, [6] the first oxazolo [5,4-f]quinoxalines were prepared by our group in 2020, [7] and notably the 8-piperidino-2-(3pyridyl) Fl-290 and the 2-(3-pyridyl)-8-thiomorpholino CD-07 derivatives identified as potent inhibitors of glycogen-synthase kinase 3 (GSK3) [8] with respective IC 50 values of about 5 and 11 nM on the isoform GSK3α [9] (Figure 1, bottom). [7] Encouraged by these promising results, our goal in the present paper is to show that 6-amino-5-iodoquinoxalines can be used as common substrates to access these three families, to evaluate the photochemical properties of these compounds and to screen their biological activities.…”

“…While a few thiazolo[5,4‐ f ]quinoxalines have been claimed in patents, [6] the first oxazolo[5,4‐ f ]quinoxalines were prepared by our group in 2020, [7] and notably the 8‐piperidino‐2‐(3‐pyridyl) Fl‐290 and the 2‐(3‐pyridyl)‐8‐thiomorpholino CD‐07 derivatives identified as potent inhibitors of glycogen‐synthase kinase 3 (GSK3) [8] with respective IC 50 values of about 5 and 11 nM on the isoform GSK3α [9] (Figure 1, bottom) [7] …”