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Title: Meridianins and Lignarenone B as Potential GSK3β Inhibitors and Inductors of Structural Neuronal Plasticity
Author: Llorach Parés, Laura
Rodriguez Urgelles, Ened
Nonell Canals, Alfons
Alberch i Vié, Jordi
Avila, Conxita
Sánchez Martínez, Melchor
Giralt Torroella, Albert
Keywords: Malaltia d'Alzheimer
Malalties neurodegeneratives
Alzheimer's disease
Neurodegenerative Diseases
Issue Date: 21-Apr-2020
Publisher: MDPI
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.
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It is part of: Biomolecules, 2020, vol. 10, num. 4, p. E639
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ISSN: 2218-273X
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Biomedicina)

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