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Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes

Autosomal dominant leukodystrophy (ADLD) is an extremely rare and fatal neurodegenerative disease due to the overexpression of the nuclear lamina component Lamin B1. Many aspects of the pathology still remain unrevealed. This work highlights the effect of Lamin B1 accumulation on different cellular...

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Autores principales: Ratti, Stefano, Rusciano, Isabella, Mongiorgi, Sara, Neri, Irene, Cappellini, Alessandra, Cortelli, Pietro, Suh, Pann-Ghill, McCubrey, James A., Manzoli, Lucia, Cocco, Lucio, Ramazzotti, Giulia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534128/
https://www.ncbi.nlm.nih.gov/pubmed/34685544
http://dx.doi.org/10.3390/cells10102566
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author Ratti, Stefano
Rusciano, Isabella
Mongiorgi, Sara
Neri, Irene
Cappellini, Alessandra
Cortelli, Pietro
Suh, Pann-Ghill
McCubrey, James A.
Manzoli, Lucia
Cocco, Lucio
Ramazzotti, Giulia
author_facet Ratti, Stefano
Rusciano, Isabella
Mongiorgi, Sara
Neri, Irene
Cappellini, Alessandra
Cortelli, Pietro
Suh, Pann-Ghill
McCubrey, James A.
Manzoli, Lucia
Cocco, Lucio
Ramazzotti, Giulia
author_sort Ratti, Stefano
collection PubMed
description Autosomal dominant leukodystrophy (ADLD) is an extremely rare and fatal neurodegenerative disease due to the overexpression of the nuclear lamina component Lamin B1. Many aspects of the pathology still remain unrevealed. This work highlights the effect of Lamin B1 accumulation on different cellular functions in an ADLD astrocytic in vitro model. Lamin B1 overexpression induces alterations in cell survival signaling pathways with GSK3β inactivation, but not the upregulation of β-catenin targets, therefore resulting in a reduction in astrocyte survival. Moreover, Lamin B1 build up affects proliferation and cell cycle progression with an increase of PPARγ and p27 and a decrease of Cyclin D1. These events are also associated to a reduction in cell viability and an induction of apoptosis. Interestingly, ADLD astrocytes trigger a tentative activation of survival pathways that are ineffective. Finally, astrocytes overexpressing Lamin B1 show increased immunoreactivity for both GFAP and vimentin together with NF-kB phosphorylation and c-Fos increase, suggesting astrocytes reactivity and substantial cellular activation. These data demonstrate that Lamin B1 accumulation is correlated to biochemical, metabolic, and morphologic remodeling, probably related to the induction of a reactive astrocytes phenotype that could be strictly associated to ADLD pathological mechanisms.
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spelling pubmed-85341282021-10-23 Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes Ratti, Stefano Rusciano, Isabella Mongiorgi, Sara Neri, Irene Cappellini, Alessandra Cortelli, Pietro Suh, Pann-Ghill McCubrey, James A. Manzoli, Lucia Cocco, Lucio Ramazzotti, Giulia Cells Article Autosomal dominant leukodystrophy (ADLD) is an extremely rare and fatal neurodegenerative disease due to the overexpression of the nuclear lamina component Lamin B1. Many aspects of the pathology still remain unrevealed. This work highlights the effect of Lamin B1 accumulation on different cellular functions in an ADLD astrocytic in vitro model. Lamin B1 overexpression induces alterations in cell survival signaling pathways with GSK3β inactivation, but not the upregulation of β-catenin targets, therefore resulting in a reduction in astrocyte survival. Moreover, Lamin B1 build up affects proliferation and cell cycle progression with an increase of PPARγ and p27 and a decrease of Cyclin D1. These events are also associated to a reduction in cell viability and an induction of apoptosis. Interestingly, ADLD astrocytes trigger a tentative activation of survival pathways that are ineffective. Finally, astrocytes overexpressing Lamin B1 show increased immunoreactivity for both GFAP and vimentin together with NF-kB phosphorylation and c-Fos increase, suggesting astrocytes reactivity and substantial cellular activation. These data demonstrate that Lamin B1 accumulation is correlated to biochemical, metabolic, and morphologic remodeling, probably related to the induction of a reactive astrocytes phenotype that could be strictly associated to ADLD pathological mechanisms. MDPI 2021-09-28 /pmc/articles/PMC8534128/ /pubmed/34685544 http://dx.doi.org/10.3390/cells10102566 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ratti, Stefano
Rusciano, Isabella
Mongiorgi, Sara
Neri, Irene
Cappellini, Alessandra
Cortelli, Pietro
Suh, Pann-Ghill
McCubrey, James A.
Manzoli, Lucia
Cocco, Lucio
Ramazzotti, Giulia
Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes
title Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes
title_full Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes
title_fullStr Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes
title_full_unstemmed Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes
title_short Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes
title_sort lamin b1 accumulation’s effects on autosomal dominant leukodystrophy (adld): induction of reactivity in the astrocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534128/
https://www.ncbi.nlm.nih.gov/pubmed/34685544
http://dx.doi.org/10.3390/cells10102566
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