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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7400170 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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