Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease - Sánchez-Danés - 2012 - EMBO Molecular Medicine - Wiley Online Library

Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease - Sánchez-Danés - 2012 - EMBO Molecular Medicine - Wiley Online Library

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

1. Adriana Sánchez-Danés¹,
2. Yvonne Richaud-Patin^2,3,†,
3. Iria Carballo-Carbajal^4,5,†,
4. Senda Jiménez-Delgado^2,3,
5. Carles Caig^5,6,
6. Sergio Mora^2,3,
7. Claudia Di Guglielmo^2,3,7,
8. Mario Ezquerra^5,6,
9. Bindiben Patel⁸,
10. Albert Giralt^5,9,10,11,
11. Josep M. Canals^5,9,10,11,
12. Maurizio Memo⁷,
13. Jordi Alberch^5,9,10,11,
14. José López-Barneo^5,12,
15. Miquel Vila^4,5,13,
16. Ana Maria Cuervo⁸,
17. Eduard Tolosa^5,6,10,11,
18. Antonella Consiglio^1,7,*,
19. Angel Raya^2,3,13,*

Article first published online: 8 MAR 2012

DOI: 10.1002/emmm.201200215

Copyright © 2012 EMBO Molecular Medicine

This is an Open Access article under the terms of the Creative Commons Attribution Non Commercial License which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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EMBO Molecular Medicine

Early View (Online Version of Record published before inclusion in an issue)

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Keywords:

• autophagy;
• disease modeling;
• LRRK2 mutation;
• neurodegeneration;
• pluripotent stem cells

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.