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Glycogen Synthase Kinase-3: A Potential Target for Drug Discovery in the Treatment of Neurodegenerative Disorders

[ Vol. 13 , Issue. 2 ]

Author(s):

Darshit B. Shah and M. Ramanathan   Pages 107 - 128 ( 22 )

Abstract:


The current review deals with the involvement of glycogen synthase kinase-3 (GSK-3) in major neurodegenerative disorders like Alzheimer’s Disease (AD), Cerebral ischemia, Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS). GSK-3 is a proline-directed serine/threonine kinase, considered as a key influencer in these pathologies. From gene to protein, every process has crucial involvement in the genesis of disease. Gene splicing of exon 8 and 9 is more distinct in the function compared to the native one. GSK-3 mRNA and protein are involved in transcribing a variety of genes that are involved in the progression of pathology. Post-translational modification of GSK-3 by multiple substrates further regulates downstream messengers and their response in multiple pathologies. This conserved functioning of GSK-3 makes it a viable target. Various competitive and non-competitive GSK-3 inhibitors slowed the progression and modified onset of disease. Inhibition of GSK-3 alters the neurobiology of disease, thereby having a beneficial effect. However, none of these inhibitors, till date found promising efficacy in reversing the state of pathology, raising questions about the mode and magnitude of inhibition. Involvement of GSK-3 in multiple signaling cascades can pull down inhibition efficacy in pathology. Efforts are needed to generate inhibitors which can block both the prime and ATP binding site or a small hydrophobic pocket defined by Ile62, Gly63, and Phe67 residues. These types of inhibitors may have better effects compared to existing ones. Inhibiting multiple targets respective to the disease concerned, along with GSK-3 inhibition may have more therapeutic benefits than inhibiting alone GSK-3 alone.

Keywords:

Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), cerebral ischemia, glycogen synthase kinase-3β (GSK-3β), neurodegenerative disorders, Parkinson’s Disease (PD).

Affiliation:

Department of Pharmacology, PSG College of Pharmacy, Coimbatore - 641004, Tamil Nadu, Department of Pharmacology, PSG College of Pharmacy, Coimbatore - 641004, Tamil Nadu

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