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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

Author Affiliations

  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 Consiglio (aconsiglio{at}pcb.ub.es) *,1,7 and
  19. Angel Raya (araya{at}ibecbarcelona.eu) *,2,3,13
  1. 1Institute for Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
  2. 2Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain
  3. 3Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER‐BBN), Spain
  4. 4Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Barcelona, Spain
  5. 5Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
  6. 6Movement Disorders Unit, Department of Neurology, Hospital Clinic of Barcelona, Barcelona, Spain
  7. 7Department of Biomedical Science and Biotechnology, University of Brescia, Brescia, Italy
  8. 8Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
  9. 9Faculty of Medicine, Department of Cell Biology, Immunology and Neuroscience, Universitat de Barcelona, Barcelona, Spain
  10. 10Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
  11. 11Cell Therapy Program, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
  12. 12Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain
  13. 13Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
  1. * Antonella Consiglio, Tel: +34 93 403 9842; Fax: +34 93 403 4570

    Angel Raya, Tel: +34 93 402 0537; Fax: +34 93 402 0183

  1. These authors contributed equally to this work.

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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.

  • Received July 15, 2011.
  • Revision received January 4, 2012.
  • Accepted January 10, 2012.
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