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Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a severe and lethal neurodegenerative disease. Upon specific point mutations in the SERPINI1gene-coding for the human protein neuroserpin (NS) the resulting pathologic NS variants polymerize and accumulate within the endoplasmic re...

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Autores principales: Visentin, Cristina, Musso, Loana, Broggini, Luca, Bonato, Francesca, Russo, Rosaria, Moriconi, Claudia, Bolognesi, Martino, Miranda, Elena, Dallavalle, Sabrina, Passarella, Daniele, Ricagno, Stefano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400170/
https://www.ncbi.nlm.nih.gov/pubmed/32664592
http://dx.doi.org/10.3390/life10070111
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author Visentin, Cristina
Musso, Loana
Broggini, Luca
Bonato, Francesca
Russo, Rosaria
Moriconi, Claudia
Bolognesi, Martino
Miranda, Elena
Dallavalle, Sabrina
Passarella, Daniele
Ricagno, Stefano
author_facet Visentin, Cristina
Musso, Loana
Broggini, Luca
Bonato, Francesca
Russo, Rosaria
Moriconi, Claudia
Bolognesi, Martino
Miranda, Elena
Dallavalle, Sabrina
Passarella, Daniele
Ricagno, Stefano
author_sort Visentin, Cristina
collection PubMed
description Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a severe and lethal neurodegenerative disease. Upon specific point mutations in the SERPINI1gene-coding for the human protein neuroserpin (NS) the resulting pathologic NS variants polymerize and accumulate within the endoplasmic reticulum of neurons in the central nervous system. To date, embelin (EMB) is the only known inhibitor of NS polymerization in vitro. This molecule is capable of preventing NS polymerization and dissolving preformed polymers. Here, we show that lowering EMB concentration results in increasing size of NS oligomers in vitro. Moreover, we observe that in cells expressing NS, the polymerization of G392E NS is reduced, but this effect is mediated by an increased proteasomal degradation rather than polymerization impairment. For these reasons we designed a systematic chemical evolution of the EMB scaffold aimed to improve its anti-polymerization properties. The effect of EMB analogs against NS polymerization was assessed in vitro. None of the EMB analogs displayed an anti-polymerization activity better than the one reported for EMB, indicating that the EMB–NS interaction surface is very specific and highly optimized. Thus, our results indicate that EMB is, to date, still the best candidate for developing a treatment against NS polymerization.
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spelling pubmed-74001702020-08-23 Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors Visentin, Cristina Musso, Loana Broggini, Luca Bonato, Francesca Russo, Rosaria Moriconi, Claudia Bolognesi, Martino Miranda, Elena Dallavalle, Sabrina Passarella, Daniele Ricagno, Stefano Life (Basel) Article Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a severe and lethal neurodegenerative disease. Upon specific point mutations in the SERPINI1gene-coding for the human protein neuroserpin (NS) the resulting pathologic NS variants polymerize and accumulate within the endoplasmic reticulum of neurons in the central nervous system. To date, embelin (EMB) is the only known inhibitor of NS polymerization in vitro. This molecule is capable of preventing NS polymerization and dissolving preformed polymers. Here, we show that lowering EMB concentration results in increasing size of NS oligomers in vitro. Moreover, we observe that in cells expressing NS, the polymerization of G392E NS is reduced, but this effect is mediated by an increased proteasomal degradation rather than polymerization impairment. For these reasons we designed a systematic chemical evolution of the EMB scaffold aimed to improve its anti-polymerization properties. The effect of EMB analogs against NS polymerization was assessed in vitro. None of the EMB analogs displayed an anti-polymerization activity better than the one reported for EMB, indicating that the EMB–NS interaction surface is very specific and highly optimized. Thus, our results indicate that EMB is, to date, still the best candidate for developing a treatment against NS polymerization. MDPI 2020-07-11 /pmc/articles/PMC7400170/ /pubmed/32664592 http://dx.doi.org/10.3390/life10070111 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Visentin, Cristina
Musso, Loana
Broggini, Luca
Bonato, Francesca
Russo, Rosaria
Moriconi, Claudia
Bolognesi, Martino
Miranda, Elena
Dallavalle, Sabrina
Passarella, Daniele
Ricagno, Stefano
Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors
title Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors
title_full Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors
title_fullStr Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors
title_full_unstemmed Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors
title_short Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors
title_sort embelin as lead compound for new neuroserpin polymerization inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400170/
https://www.ncbi.nlm.nih.gov/pubmed/32664592
http://dx.doi.org/10.3390/life10070111
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