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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Detalles Bibliográficos
Autores: Sánchez Danés, Adriana, Richaud-Patin, Yvonne, Carballo Carbajal, Iria, Jiménez Delgado, Senda, Caig, Carles, Mora, Sergio, Di Guglielmo, Claudia, Ezquerra Trabalón, Mario, Patel, Bindiben, Giralt Torroella, Albert, Canals i Coll, Josep M., Memo, Maurizio, Alberch i Vié, Jordi, 1959-, López Barneo, José, Vila Farré, Miquel, Cuervo, Ana Maria, Tolosa, Eduardo, Consiglio, Antonella, Raya Chamorro, Ángel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2012
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/133843
Acceso en línea:https://hdl.handle.net/2445/133843
Access Level:acceso abierto
Palabra clave:Dopamina
Metabolisme
Fenotip
Genètica
Neurones
Malaltia de Parkinson
Patologia
Cèl·lules mare
Dopamine
Metabolism
Phenotype
Genetics
Neurons
Parkinson's disease
Pathology
Stem cells
Descripción
Sumario: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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