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

Laura Llorach-Pares,Albert Giralt,Melchor Sanchez-Martinez,Alfons Nonell-Canals,Conxita Avila,Ened Rodriguez-Urgelles,Jordi Alberch

doi:10.3390/biom10040639

Abstract

Glycogen Synthase Kinase 3 (GSK3) is an essential protein, with a relevant role in many diseases such as diabetes, cancer and neurodegenerative disorders. Particularly, the isoform GSK3β is related to pathologies such as Alzheimer’s disease (AD). This enzyme constitutes a very interesting target for the discovery and/or design of new therapeutic agents against AD due to its relation to the hyperphosphorylation of the microtubule-associated protein tau (MAPT), and therefore, its contribution to neurofibrillary tangles (NFT) formation. An in silico target profiling study identified two marine molecular families, the indole alkaloids meridianins from the tunicate genus Aplidium, and lignarenones, the secondary metabolites of the shelled cephalaspidean mollusc Scaphander lignarius, as possible GSK3β inhibitors. The analysis of the surface of GSK3β, aimed to find possible binding regions, and the subsequent in silico binding studies revealed that both marine molecular families can act over the ATP and/or substrate binding regions. The predicted inhibitory potential of the molecules from these two chemical families was experimentally validated in vitro by showing a ~50% of increased Ser9 phosphorylation levels of the GSK3β protein. Furthermore, we determined that molecules from both molecular families potentiate structural neuronal plasticity in vitro. These results allow us to suggest that meridianins and lignarenone B could be used as possible therapeutic candidates for the treatment of GSK3β involved pathologies, such as AD.

Highlights

Glycogen Synthase Kinase 3 (GSK3) is a key contributor to the abnormal phosphorylation of the microtubule-binding protein tau in the process thought to cause neurofibrillary tangle (NFT) formation in Alzheimer’s disease (AD) [1,2]
Most of the pockets found here had been previously described over a different crystal structure [14], reinforcing the output of the performed cavity detection
Due to the interest in developing allosteric inhibitors and the high number of cavities found on the surface of GSK3β, it is relevant to study the capacity of meridianins and lignarenones to act as allosteric inhibitors as well as adenosine triphosphate (ATP)-competitive inhibitors

Summary

Introduction

Glycogen Synthase Kinase 3 (GSK3) is a key contributor to the abnormal phosphorylation of the microtubule-binding protein tau in the process thought to cause neurofibrillary tangle (NFT) formation in Alzheimer’s disease (AD) [1,2]. GSK3 is an ubiquitous serine (Ser)/threonine (Thr) protein kinase and is involved in the transfer of a phosphate group from adenosine triphosphate (ATP) to Ser and Thraminoacid residues of target substrates. GSK3 is constitutively active, its substrates usually need to be pre-phosphorylated by another kinase, and it is inhibited, rather than activated, in response to stimulation of the insulin and Wnt pathways [3,4,5]. The predominant hypothesis in AD suggests that the activity of phosphatases and kinases, in particular GSK3β, is affected by amyloid peptides. Changes in kinase activity of GSK3β are an intrinsic aspect of the pathological problem in AD, as they negatively affect, even interrupting, synaptic signals essential for learning and memory [10]. GSK3 activity can be regulated by serine 9/21 phosphorylation. The kinase can be phosphorylated at additional different sites, but their regulatory outcomes remain unclear [3]

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