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

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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.

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Funding

This research work was funded by the Council of Scientific and Industrial Research (CSIR) Network grant miND (BSC0115) to Dr. Shubha Shukla. The authors would like to thank Director of CSIR-Central Drug Research Institute (CDRI), Lucknow, India for constant support and direction in the study. Sonu Singh is supported by a research fellowship from Indian Council of Medical Research (ICMR), New Delhi, India. Akanksha Mishra, Virendra Tiwari, Jitendra Singh, and Parul are supported by a research fellowship from CSIR, New Delhi, India. The CSIR-CDRI manuscript communication number for this article is 9608.

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  1. Division of Pharmacology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh, 226031, India

    Sonu Singh, Akanksha Mishra, Sachi Bharti, Virendra Tiwari, Jitendra Singh,  Parul & Shubha Shukla

  2. Academy of Scientific and Innovative Research, New Delhi, India

    Akanksha Mishra & Shubha Shukla

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  1. Sonu Singh
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Singh, S., Mishra, A., Bharti, S. et al. Glycogen Synthase Kinase-3β Regulates Equilibrium Between Neurogenesis and Gliogenesis in Rat Model of Parkinson’s Disease: a Crosstalk with Wnt and Notch Signaling. Mol Neurobiol 55, 6500–6517 (2018). https://doi.org/10.1007/s12035-017-0860-4

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