Glycogen Synthase Kinase-3β Regulates Equilibrium Between Neurogenesis and Gliogenesis in Rat Model of Parkinson’s Disease: a Crosstalk with Wnt and Notch Signaling

Abstract

Neurogenesis involves generation of functional newborn neurons from neural stem cells (NSCs). Insufficient formation or accelerated degeneration of newborn neurons may contribute to the severity of motor/nonmotor symptoms of Parkinson's disease (PD). However, the functional role of adult neurogenesis in PD is yet not explored and whether glycogen synthase kinase-3β (GSK-3β) affects multiple steps of adult neurogenesis in PD is still unknown. We investigated the possible underlying molecular mechanism of impaired adult neurogenesis associated with PD. Herein, we show that single intra-medial forebrain bundle (MFB) injection of 6-hydroxydopamine (6-OHDA) efficiently induced long-term activation of GSK-3β and reduced NSC self-renewal, proliferation, neuronal migration, and neuronal differentiation accompanied with increased astrogenesis in subventricular zone (SVZ) and hippocampal dentate gyrus (DG). Indeed, 6-OHDA also delayed maturation of neuroblasts in the DG as witnessed by their reduced dendritic length and arborization. Using a pharmacological approach to inhibit GSK-3β activation by specific inhibitor SB216763, we show that GSK-3β inhibition enhances radial glial cells, NSC proliferation, self-renewal in the SVZ, and the subgranular zone (SGZ) in the rat PD model. Pharmacological inhibition of GSK-3β activity enhances neuroblast population in SVZ and SGZ and promotes migration of neuroblasts towards the rostral migratory stream and lesioned striatum from dorsal SVZ and lateral SVZ, respectively, in PD model. GSK-3β inhibition enhances dendritic arborization and survival of granular neurons and stimulates NSC differentiation towards the neuronal phenotype in DG of PD model. The aforementioned effects of GSK-3β involve a crosstalk between Wnt/β-catenin and Notch signaling pathways that are known to regulate NSC dynamics.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…Corroborating our earlier findings, a number of recent studies have highlighted the critical importance of WβC crosstalk with survival and inflammatory pathways in inciting neurogenesis and neurorepair Kalamakis et al, 2019;Kase, Otsu, Shimazaki, & Okano, 2019;Mishra et al, 2019;Morrow & Moore, 2019;Ray et al, 2018;Singh, Mishra, Bharti, et al, 2018b;Singh, Mishra, Mohanbhai, et al, 2018a;Singh, Mishra, & Shukla, 2016).…”

“…Owing to the potential associations between the Wnt pathway and mitochondrial dynamics, apoptosis, and the cell cycle, which in turn affect NSC self‐renewal and differentiation (Beckervordersandforth, ; Beckervordersandforth et al, ; Chandle et al, ; Chong, Shang, Hou, & Maiese, ; Rasmussen et al, ; Richetin et al, ; Singh, Mishra, Bharti, et al, ; Walter et al, ), we herein highlight the role of WβC ‐ signalling and its crosstalk with astrocyte‐ and microglial‐derived oxidative and inflammatory pathways in the regulation of adult neurogenesis in PD. Particular attention is paid to the exacerbated inflammation and oxidative stress associated with the upregulation of endogenous Wnt‐inhibitors.…”

“…Here, activation of WβC‐signalling using the specific GSK‐3β inhibitor SB216763 efficiently counteracted the 6‐OHDA‐induced neurogenic impairment at both the SVZ and SGZ levels. In the hippocampus, GSK‐3β inhibition enhanced dendritic arborization and survival of granular neurons and stimulated NSC differentiation towards the neuronal phenotype in the DG (Singh et al, ; Singh, Mishra, Mohanbhai, et al, ).…”

“…After our first studies demonstrating dysregulated WβC‐signalling in the MPTP mouse model of PD, both in vivo and in vitro (L'Episcopo et al, ;b), more recent reports corroborated the key role of WβC in the physiopathology of PD (see Marchetti, for an up‐to‐date review). Among others, Singh, Mishra, Bharti, et al () used short hairpin (sh)RNA‐lentiviruses to genetically knockdown AXIN2 to up‐regulate WβC‐signalling in the SNpc, in 6‐OHDA‐induced parkinsonism rats. Not surprisingly, genetic knockdown of AXIN2 (a WβC‐pathway suppressor, see Section 2), up‐regulated WβC‐signalling with beneficial consequences for DAergic neurogenesis (Singh, Mishra, Bharti, et al, ).…”

“…Among others, Singh, Mishra, Bharti, et al () used short hairpin (sh)RNA‐lentiviruses to genetically knockdown AXIN2 to up‐regulate WβC‐signalling in the SNpc, in 6‐OHDA‐induced parkinsonism rats. Not surprisingly, genetic knockdown of AXIN2 (a WβC‐pathway suppressor, see Section 2), up‐regulated WβC‐signalling with beneficial consequences for DAergic neurogenesis (Singh, Mishra, Bharti, et al, ).…”