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p27(Kip1) regulates alpha-synuclein expression

Alpha-synuclein (α-SYN) is the main component of anomalous protein aggregates (Lewy bodies) that play a crucial role in several neurodegenerative diseases (synucleinopathies) like Parkinson’s disease and multiple system atrophy. However, the mechanisms involved in its transcriptional regulation are...

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Autores principales: Gallastegui, Edurne, Domuro, Carla, Serratosa, Joan, Larrieux, Alejandra, Sin, Laura, Martinez, Jonatan, Besson, Arnaud, Morante-Redolat, José Manuel, Orlando, Serena, Aligue, Rosa, Fariñas, Isabel, Pujol, María Jesús, Bachs, Oriol
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893246/
https://www.ncbi.nlm.nih.gov/pubmed/29662651
http://dx.doi.org/10.18632/oncotarget.24687
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author Gallastegui, Edurne
Domuro, Carla
Serratosa, Joan
Larrieux, Alejandra
Sin, Laura
Martinez, Jonatan
Besson, Arnaud
Morante-Redolat, José Manuel
Orlando, Serena
Aligue, Rosa
Fariñas, Isabel
Pujol, María Jesús
Bachs, Oriol
author_facet Gallastegui, Edurne
Domuro, Carla
Serratosa, Joan
Larrieux, Alejandra
Sin, Laura
Martinez, Jonatan
Besson, Arnaud
Morante-Redolat, José Manuel
Orlando, Serena
Aligue, Rosa
Fariñas, Isabel
Pujol, María Jesús
Bachs, Oriol
author_sort Gallastegui, Edurne
collection PubMed
description Alpha-synuclein (α-SYN) is the main component of anomalous protein aggregates (Lewy bodies) that play a crucial role in several neurodegenerative diseases (synucleinopathies) like Parkinson’s disease and multiple system atrophy. However, the mechanisms involved in its transcriptional regulation are poorly understood. We investigated here the role of the cyclin-dependent kinase (Cdk) inhibitor and transcriptional regulator p27(Kip1) (p27) in the regulation of α-SYN expression. We observed that selective deletion of p27 by CRISPR/Cas9 technology in neural cells resulted in increased levels of α-SYN. Knock-down of the member of the same family p21(Cip1) (p21) also led to increased α-SYN levels, indicating that p27 and p21 collaborate in the repression of α-SYN transcription. We demonstrated that this repression is mediated by the transcription factor E2F4 and the member of the retinoblastoma protein family p130 and that it is dependent of Cdk activity. Chromatin immunoprecipitation analysis revealed specific binding sites for p27, p21 and E2F4 in the proximal α-SYN gene promoter. Finally, luciferase assays revealed a direct action of p27, p21 and E2F4 in α-SYN gene expression. Our findings reveal for the first time a negative regulatory mechanism of α-SYN expression, suggesting a putative role for cell cycle regulators in the etiology of synucleinopathies.
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spelling pubmed-58932462018-04-16 p27(Kip1) regulates alpha-synuclein expression Gallastegui, Edurne Domuro, Carla Serratosa, Joan Larrieux, Alejandra Sin, Laura Martinez, Jonatan Besson, Arnaud Morante-Redolat, José Manuel Orlando, Serena Aligue, Rosa Fariñas, Isabel Pujol, María Jesús Bachs, Oriol Oncotarget Research Paper Alpha-synuclein (α-SYN) is the main component of anomalous protein aggregates (Lewy bodies) that play a crucial role in several neurodegenerative diseases (synucleinopathies) like Parkinson’s disease and multiple system atrophy. However, the mechanisms involved in its transcriptional regulation are poorly understood. We investigated here the role of the cyclin-dependent kinase (Cdk) inhibitor and transcriptional regulator p27(Kip1) (p27) in the regulation of α-SYN expression. We observed that selective deletion of p27 by CRISPR/Cas9 technology in neural cells resulted in increased levels of α-SYN. Knock-down of the member of the same family p21(Cip1) (p21) also led to increased α-SYN levels, indicating that p27 and p21 collaborate in the repression of α-SYN transcription. We demonstrated that this repression is mediated by the transcription factor E2F4 and the member of the retinoblastoma protein family p130 and that it is dependent of Cdk activity. Chromatin immunoprecipitation analysis revealed specific binding sites for p27, p21 and E2F4 in the proximal α-SYN gene promoter. Finally, luciferase assays revealed a direct action of p27, p21 and E2F4 in α-SYN gene expression. Our findings reveal for the first time a negative regulatory mechanism of α-SYN expression, suggesting a putative role for cell cycle regulators in the etiology of synucleinopathies. Impact Journals LLC 2018-03-27 /pmc/articles/PMC5893246/ /pubmed/29662651 http://dx.doi.org/10.18632/oncotarget.24687 Text en Copyright: © 2018 Gallastegui et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Gallastegui, Edurne
Domuro, Carla
Serratosa, Joan
Larrieux, Alejandra
Sin, Laura
Martinez, Jonatan
Besson, Arnaud
Morante-Redolat, José Manuel
Orlando, Serena
Aligue, Rosa
Fariñas, Isabel
Pujol, María Jesús
Bachs, Oriol
p27(Kip1) regulates alpha-synuclein expression
title p27(Kip1) regulates alpha-synuclein expression
title_full p27(Kip1) regulates alpha-synuclein expression
title_fullStr p27(Kip1) regulates alpha-synuclein expression
title_full_unstemmed p27(Kip1) regulates alpha-synuclein expression
title_short p27(Kip1) regulates alpha-synuclein expression
title_sort p27(kip1) regulates alpha-synuclein expression
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893246/
https://www.ncbi.nlm.nih.gov/pubmed/29662651
http://dx.doi.org/10.18632/oncotarget.24687
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