Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782238861139640320 |
---|---|
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. |
format | Online Article Text |
id | pubmed-3403296 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | WILEY-VCH Verlag |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT sanchezdanesadriana diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT richaudpatinyvonne diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT carballocarbajaliria diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT jimenezdelgadosenda diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT caigcarles diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT morasergio diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT diguglielmoclaudia diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT ezquerramario diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT patelbindiben diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT giraltalbert diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT canalsjosepm diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT memomaurizio diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT alberchjordi diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT lopezbarneojose diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT vilamiquel diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT cuervoanamaria diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT tolosaeduard diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT consiglioantonella diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease AT rayaangel diseasespecificphenotypesindopamineneuronsfromhumanipsbasedmodelsofgeneticandsporadicparkinsonsdisease |