Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives
Background: Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the protein quality control (PQC) system. The PQC system is composed by chaperones and the degradative systems (proteasome and autophagy)....
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Format: | Article |
Language: | English |
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MDPI AG
2020-05-01
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Series: | International Journal of Molecular Sciences |
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Online Access: | https://www.mdpi.com/1422-0067/21/10/3443 |
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doaj-76345ee1271a4433a8e8ddcc91c25589 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Paola Rusmini Riccardo Cristofani Barbara Tedesco Veronica Ferrari Elio Messi Margherita Piccolella Elena Casarotto Marta Chierichetti Maria Elena Cicardi Mariarita Galbiati Cristina Geroni Paolo Lombardi Valeria Crippa Angelo Poletti |
spellingShingle |
Paola Rusmini Riccardo Cristofani Barbara Tedesco Veronica Ferrari Elio Messi Margherita Piccolella Elena Casarotto Marta Chierichetti Maria Elena Cicardi Mariarita Galbiati Cristina Geroni Paolo Lombardi Valeria Crippa Angelo Poletti Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives International Journal of Molecular Sciences misfolding neurodegeneration spinal and bulbar muscular atrophy protein aggregation berberine amyotrophic lateral sclerosis |
author_facet |
Paola Rusmini Riccardo Cristofani Barbara Tedesco Veronica Ferrari Elio Messi Margherita Piccolella Elena Casarotto Marta Chierichetti Maria Elena Cicardi Mariarita Galbiati Cristina Geroni Paolo Lombardi Valeria Crippa Angelo Poletti |
author_sort |
Paola Rusmini |
title |
Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives |
title_short |
Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives |
title_full |
Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives |
title_fullStr |
Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives |
title_full_unstemmed |
Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives |
title_sort |
enhanced clearance of neurotoxic misfolded proteins by the natural compound berberine and its derivatives |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-05-01 |
description |
Background: Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the protein quality control (PQC) system. The PQC system is composed by chaperones and the degradative systems (proteasome and autophagy). Mutant proteins that misfold are potentially neurotoxic, thus strategies aimed at preventing their aggregation or at enhancing their clearance are emerging as interesting therapeutic targets for NDs. Methods: We tested the natural alkaloid berberine (BBR) and some derivatives for their capability to enhance misfolded protein clearance in cell models of NDs, evaluating which degradative pathway mediates their action. Results: We found that both BBR and its semisynthetic derivatives promote degradation of mutant androgen receptor (ARpolyQ) causative of spinal and bulbar muscular atrophy, acting mainly via proteasome and preventing ARpolyQ aggregation. Overlapping effects were observed on other misfolded proteins causative of amyotrophic lateral sclerosis, frontotemporal-lobar degeneration or Huntington disease, but with selective and specific action against each different mutant protein. Conclusions: BBR and its analogues induce the clearance of misfolded proteins responsible for NDs, representing potential therapeutic tools to counteract these fatal disorders. |
topic |
misfolding neurodegeneration spinal and bulbar muscular atrophy protein aggregation berberine amyotrophic lateral sclerosis |
url |
https://www.mdpi.com/1422-0067/21/10/3443 |
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doaj-76345ee1271a4433a8e8ddcc91c255892020-11-25T02:31:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-05-01213443344310.3390/ijms21103443Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its DerivativesPaola Rusmini0Riccardo Cristofani1Barbara Tedesco2Veronica Ferrari3Elio Messi4Margherita Piccolella5Elena Casarotto6Marta Chierichetti7Maria Elena Cicardi8Mariarita Galbiati9Cristina Geroni10Paolo Lombardi11Valeria Crippa12Angelo Poletti13Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyNaxospharma srl, 20026 Novate Milanese, Milan, ItalyNaxospharma srl, 20026 Novate Milanese, Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Dipartimento di Eccellenza 2018-2022, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, ItalyBackground: Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the protein quality control (PQC) system. The PQC system is composed by chaperones and the degradative systems (proteasome and autophagy). Mutant proteins that misfold are potentially neurotoxic, thus strategies aimed at preventing their aggregation or at enhancing their clearance are emerging as interesting therapeutic targets for NDs. Methods: We tested the natural alkaloid berberine (BBR) and some derivatives for their capability to enhance misfolded protein clearance in cell models of NDs, evaluating which degradative pathway mediates their action. Results: We found that both BBR and its semisynthetic derivatives promote degradation of mutant androgen receptor (ARpolyQ) causative of spinal and bulbar muscular atrophy, acting mainly via proteasome and preventing ARpolyQ aggregation. Overlapping effects were observed on other misfolded proteins causative of amyotrophic lateral sclerosis, frontotemporal-lobar degeneration or Huntington disease, but with selective and specific action against each different mutant protein. Conclusions: BBR and its analogues induce the clearance of misfolded proteins responsible for NDs, representing potential therapeutic tools to counteract these fatal disorders.https://www.mdpi.com/1422-0067/21/10/3443misfoldingneurodegenerationspinal and bulbar muscular atrophyprotein aggregationberberineamyotrophic lateral sclerosis |