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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-Patin2,3,†,
  3. Iria Carballo-Carbajal4,5,†,
  4. Senda Jiménez-Delgado2,3,
  5. Carles Caig5,6,
  6. Sergio Mora2,3,
  7. Claudia Di Guglielmo2,3,7,
  8. Mario Ezquerra5,6,
  9. Bindiben Patel8,
  10. Albert Giralt5,9,10,11,
  11. Josep M. Canals5,9,10,11,
  12. Maurizio Memo7,
  13. Jordi Alberch5,9,10,11,
  14. José López-Barneo5,12,
  15. Miquel Vila4,5,13,
  16. Ana Maria Cuervo8,
  17. Eduard Tolosa5,6,10,11,
  18. Antonella Consiglio1,7,*,
  19. Angel Raya2,3,13,*

Article first published online: 8 MAR 2012

DOI: 10.1002/emmm.201200215

Issue

EMBO Molecular Medicine

EMBO Molecular Medicine

Volume 4, Issue 5, pages 380–395, May 2012

Additional Information

How to Cite

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. and Raya, A. (2012), Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol Med, 4: 380–395. doi: 10.1002/emmm.201200215

Author Information

  1. 1

    Institute for Biomedicine (IBUB), University of Barcelona, Barcelona, Spain

  2. 2

    Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain

  3. 3

    Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain

  4. 4

    Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Barcelona, Spain

  5. 5

    Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain

  6. 6

    Movement Disorders Unit, Department of Neurology, Hospital Clinic of Barcelona, Barcelona, Spain

  7. 7

    Department of Biomedical Science and Biotechnology, University of Brescia, Brescia, Italy

  8. 8

    Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA

  9. 9

    Faculty of Medicine, Department of Cell Biology, Immunology and Neuroscience, Universitat de Barcelona, Barcelona, Spain

  10. 10

    Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain

  11. 11

    Cell Therapy Program, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain

  12. 12

    Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain

  13. 13

    Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

  1. †

    These authors contributed equally to this work.

*Tel: +34 93 403 9842; Fax: +34 93 403 4570

  1. †

    These authors contributed equally to this work.

Publication History

  1. Issue published online: 3 MAY 2012
  2. Article first published online: 8 MAR 2012
  3. Manuscript Accepted: 10 JAN 2012
  4. Manuscript Revised: 4 JAN 2012
  5. Manuscript Received: 15 JUL 2011

Funded by

  • MICINN. Grant Numbers: BFU2009-13277, PLE2009-0144, ACI2010-1117 to AR, RyC-2008-02772, BFU2010-21823 to AC, SAF2008-04360, to JA, SAF2009-07774, PLE2009-0089, to JMC
  • FIS. Grant Numbers: PI10/00849 to MV, RD06/0010/0006 to JMC
  • NIH/NIA. Grant Number: AG031782/AG038072

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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.

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