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

Adriana Sánchez-Danés, Yvonne Richaud-Patin, Iria Carballo-Carbajal, Senda Jiménez-Delgado, Carles Caig, Sergio Mora, Claudia Di Guglielmo, Mario Ezquerra, Bindiben Patel, Albert Giralt, Josep M. Canals, Maurizio Memo, Jordi Alberch, José López-Barneo, Miquel Vila, Ana Maria Cuervo, Eduard Tolosa, Antonella Consiglio, Angel Raya

Research output: Contribution to journalArticle

348 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)380-395
Number of pages16
JournalEMBO Molecular Medicine
Volume4
Issue number5
DOIs
StatePublished - May 1 2012

Keywords

  • Autophagy
  • Disease modeling
  • LRRK2 mutation
  • Neurodegeneration
  • Pluripotent stem cells

ASJC Scopus subject areas

  • Molecular Medicine

Fingerprint Dive into the research topics of 'Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease'. Together they form a unique fingerprint.

  • Cite this

    Sánchez-Danés, A., Richaud-Patin, Y., Carballo-Carbajal, I., Jiménez-Delgado, S., Caig, C., Mora, S., Di Guglielmo, C., Ezquerra, M., Patel, B., Giralt, A., Canals, J. M., Memo, M., Alberch, J., López-Barneo, J., Vila, M., Cuervo, A. M., Tolosa, E., Consiglio, A., & Raya, A. (2012). Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Molecular Medicine, 4(5), 380-395. https://doi.org/10.1002/emmm.201200215