Association of glycogen synthase kinase-3β with Parkinson’s disease (Review)

Abstract

Glycogen synthase kinase-3 (GSK-3) is a pleiotropic serine/threonine protein kinase found in almost all eukaryotes. It is structurally highly conserved and has been identified as a multifaceted enzyme affecting a wide range of biological functions, including gene expression and cellular processes. There are two closely related isoforms of GSK-3; GSK-3α and GSK-3β. The latter appears to play crucial roles in regulating the pathogenesis of diverse diseases, including neurodegenerative disease. The present review focuses on the involvement of this protein in Parkinson’s disease (PD), a common neurodegenerative disorder characterized by the gradually progressive and selective loss of dopaminergic neurons, and by intracellular inclusions known as Lewy bodies (LBs) expressed in surviving neurons of the substantia nigra (SN). GSK-3β is involved in multiple signaling pathways and has several phosphorylation targets. Numerous apoptotic conditions can be facilitated by the GSK-3β signaling pathways. Studies have shown that GSK-3β inhibition protects the dopaminergic neurons from various stress-induced injuries, indicating the involvement of GSK-3β in PD pathogenesis. However, the underlying mechanisms of the protective effect of GSK-3β inhibition on dopaminergic neurons in PD is not completely understood. Multiple pathological events have been recognized to be responsible for the loss of dopaminergic neurons in PD, including mitochondrial dysfunction, oxidative stress, protein aggregation and neuroinflammation. The present review stresses the regulatory roles of GSK-3β in these events and in dopaminergic neuron degeneration, in an attempt to gain an improved understanding of the underlying mechanisms and to provide a potential effective therapeutic target for PD.

α-Synuclein binds to the ER–mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production

“…However, for TDP-43 and FUS, this breaking involves activation of GSK-3β; GSK-3β is a regulator of the VAPB–PTPIP51 interaction and so controls ER–mitochondria associations and Ca 2+ exchange [78, 79]. GSK-3β has been linked to α-synuclein and Parkinson’s disease [27, 54, 57] but we found no evidence that either wild-type or mutant α-synuclein expression caused activation of GSK-3β. Rather, we found that α-synuclein bound directly to VAPB.…”

Meridianins and Lignarenone B as Potential GSK3β Inhibitors and Inductors of Structural Neuronal Plasticity

“…There are two highly conserved isoforms of GSK3, GSK3α and GSK3β. Particularly, GSK3β is widely present in the brain and is associated with several neurodegenerative diseases, including Parkinson's disease (PD), AD and Huntington's disease (HD) [6][7][8][9]. The predominant hypothesis in AD suggests that the activity of phosphatases and kinases, in particular GSK3β, is affected by amyloid peptides.…”

The inhibition of BDNF/TrkB/PI3K/Akt signal mediated by AG1601 promotes apoptosis in malignant glioma

“…In our study, the in vivo experiment showed that AG1601 also inhibited the related protein expression of BDNF/TrkB/PI3K/Akt signal in glioma, including BDNF, TrkB, PI3K, Akt, p‐Akt, and CREB (Figure A‐G). It was suggested that numerous apoptotic conditions could be facilitated by the GSK‐3β signaling pathways, and GSK‐3β promoted cell apoptosis . The GSK‐3β was inactivated by phosphorylation via PI3K/Akt signal, and the inactivation of GSK‐3β (p‐GSK‐3β) could promote angiogenesis and suppress the apoptosis of cells .…”

“…It was suggested that numerous apoptotic conditions could be facilitated by the GSK-3β signaling pathways, and GSK-3β promoted cell apoptosis. 30 The GSK-3β was inactivated by phosphorylation via PI3K/Akt signal, and the inactivation of GSK-3β (p-GSK-3β) could promote angiogenesis and suppress the apoptosis of cells. 31 It showed that p-GSK-3β in C6 cells was significantly inhibited by AG1601 in vitro (Figure 7A,E) and in vivo (Figure 2A,E).…”