TY - JOUR
T1 - Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease
AU - Sánchez-Danés, Adriana
AU - Richaud-Patin, Yvonne
AU - Carballo-Carbajal, Iria
AU - Jiménez-Delgado, Senda
AU - Caig, Carles
AU - Mora, Sergio
AU - Di Guglielmo, Claudia
AU - Ezquerra, Mario
AU - Patel, Bindiben
AU - Giralt, Albert
AU - Canals, Josep M.
AU - Memo, Maurizio
AU - Alberch, Jordi
AU - López-Barneo, José
AU - Vila, Miquel
AU - Cuervo, Ana Maria
AU - Tolosa, Eduard
AU - Consiglio, Antonella
AU - Raya, Angel
PY - 2012/5
Y1 - 2012/5
N2 - 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.
AB - 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.
KW - Autophagy
KW - Disease modeling
KW - LRRK2 mutation
KW - Neurodegeneration
KW - Pluripotent stem cells
UR - http://www.scopus.com/inward/record.url?scp=84860510280&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860510280&partnerID=8YFLogxK
U2 - 10.1002/emmm.201200215
DO - 10.1002/emmm.201200215
M3 - Article
C2 - 22407749
AN - SCOPUS:84860510280
SN - 1757-4676
VL - 4
SP - 380
EP - 395
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 5
ER -