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Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease

Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathi...

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Autores principales: Sánchez-Danés, Adriana, Richaud-Patin, Yvonne, Carballo-Carbajal, Iria, Jiménez-Delgado, Senda, Caig, Carles, Mora, Sergio, Di Guglielmo, Claudia, Ezquerra, Mario, Patel, Bindiben, Giralt, Albert, Canals, Josep M, Memo, Maurizio, Alberch, Jordi, López-Barneo, José, Vila, Miquel, Cuervo, Ana Maria, Tolosa, Eduard, Consiglio, Antonella, Raya, Angel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: WILEY-VCH Verlag 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403296/
https://www.ncbi.nlm.nih.gov/pubmed/22407749
http://dx.doi.org/10.1002/emmm.201200215
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author Sánchez-Danés, Adriana
Richaud-Patin, Yvonne
Carballo-Carbajal, Iria
Jiménez-Delgado, Senda
Caig, Carles
Mora, Sergio
Di Guglielmo, Claudia
Ezquerra, Mario
Patel, Bindiben
Giralt, Albert
Canals, Josep M
Memo, Maurizio
Alberch, Jordi
López-Barneo, José
Vila, Miquel
Cuervo, Ana Maria
Tolosa, Eduard
Consiglio, Antonella
Raya, Angel
author_facet Sánchez-Danés, Adriana
Richaud-Patin, Yvonne
Carballo-Carbajal, Iria
Jiménez-Delgado, Senda
Caig, Carles
Mora, Sergio
Di Guglielmo, Claudia
Ezquerra, Mario
Patel, Bindiben
Giralt, Albert
Canals, Josep M
Memo, Maurizio
Alberch, Jordi
López-Barneo, José
Vila, Miquel
Cuervo, Ana Maria
Tolosa, Eduard
Consiglio, Antonella
Raya, Angel
author_sort Sánchez-Danés, Adriana
collection PubMed
description Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type.
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spelling pubmed-34032962012-09-17 Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease Sánchez-Danés, Adriana Richaud-Patin, Yvonne Carballo-Carbajal, Iria Jiménez-Delgado, Senda Caig, Carles Mora, Sergio Di Guglielmo, Claudia Ezquerra, Mario Patel, Bindiben Giralt, Albert Canals, Josep M Memo, Maurizio Alberch, Jordi López-Barneo, José Vila, Miquel Cuervo, Ana Maria Tolosa, Eduard Consiglio, Antonella Raya, Angel EMBO Mol Med Research Articles Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type. WILEY-VCH Verlag 2012-05 /pmc/articles/PMC3403296/ /pubmed/22407749 http://dx.doi.org/10.1002/emmm.201200215 Text en Copyright © 2012 EMBO Molecular Medicine
spellingShingle Research Articles
Sánchez-Danés, Adriana
Richaud-Patin, Yvonne
Carballo-Carbajal, Iria
Jiménez-Delgado, Senda
Caig, Carles
Mora, Sergio
Di Guglielmo, Claudia
Ezquerra, Mario
Patel, Bindiben
Giralt, Albert
Canals, Josep M
Memo, Maurizio
Alberch, Jordi
López-Barneo, José
Vila, Miquel
Cuervo, Ana Maria
Tolosa, Eduard
Consiglio, Antonella
Raya, Angel
Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease
title Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease
title_full Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease
title_fullStr Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease
title_full_unstemmed Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease
title_short Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease
title_sort disease-specific phenotypes in dopamine neurons from human ips-based models of genetic and sporadic parkinson's disease
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403296/
https://www.ncbi.nlm.nih.gov/pubmed/22407749
http://dx.doi.org/10.1002/emmm.201200215
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