• Open Access

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

Authors

  • Adriana Sánchez-Danés,

    1. Institute for Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
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  • Yvonne Richaud-Patin,

    1. Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain
    2. Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain
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    • These authors contributed equally to this work.

  • Iria Carballo-Carbajal,

    1. Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Barcelona, Spain
    2. Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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    • These authors contributed equally to this work.

  • Senda Jiménez-Delgado,

    1. Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain
    2. Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain
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  • Carles Caig,

    1. Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
    2. Movement Disorders Unit, Department of Neurology, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Sergio Mora,

    1. Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain
    2. Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain
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  • Claudia Di Guglielmo,

    1. Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain
    2. Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain
    3. Department of Biomedical Science and Biotechnology, University of Brescia, Brescia, Italy
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  • Mario Ezquerra,

    1. Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
    2. Movement Disorders Unit, Department of Neurology, Hospital Clinic of Barcelona, Barcelona, Spain
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  • Bindiben Patel,

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

    1. Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
    2. Faculty of Medicine, Department of Cell Biology, Immunology and Neuroscience, Universitat de Barcelona, Barcelona, Spain
    3. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
    4. Cell Therapy Program, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
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  • Josep M. Canals,

    1. Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
    2. Faculty of Medicine, Department of Cell Biology, Immunology and Neuroscience, Universitat de Barcelona, Barcelona, Spain
    3. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
    4. Cell Therapy Program, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
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  • Maurizio Memo,

    1. Department of Biomedical Science and Biotechnology, University of Brescia, Brescia, Italy
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  • Jordi Alberch,

    1. Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
    2. Faculty of Medicine, Department of Cell Biology, Immunology and Neuroscience, Universitat de Barcelona, Barcelona, Spain
    3. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
    4. Cell Therapy Program, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
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  • José López-Barneo,

    1. Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
    2. Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain
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  • Miquel Vila,

    1. Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Barcelona, Spain
    2. Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
    3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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  • Ana Maria Cuervo,

    1. Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
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  • Eduard Tolosa,

    1. Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
    2. Movement Disorders Unit, Department of Neurology, Hospital Clinic of Barcelona, Barcelona, Spain
    3. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
    4. Cell Therapy Program, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
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  • Antonella Consiglio,

    Corresponding author
    1. Institute for Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
    2. Department of Biomedical Science and Biotechnology, University of Brescia, Brescia, Italy
    • Antonella Consiglio, Tel: +34 93 403 9842; Fax: +34 93 403 4570

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

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  • Angel Raya

    Corresponding author
    1. Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain
    2. Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain
    3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
    • Antonella Consiglio, Tel: +34 93 403 9842; Fax: +34 93 403 4570

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

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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.

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