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Stem Cell Reports. 2019 Feb 12;12(2):213-229. doi: 10.1016/j.stemcr.2018.12.011. Epub 2019 Jan 10.

Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease.

Author information

1
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain.
2
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain; Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona 08908, Spain.
3
Institute for Research in Biomedicine (IRB), Carrer Baldiri Reixac 10, Barcelona 08028, Spain.
4
Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona 08908, Spain; Centre for Networked Biomedical Research on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid 28029, Spain.
5
Centre Nacional d'Anàlisi Genòmica (CNAG-CRG), Parc Científic de Barcelona, Barcelona 08028, Spain.
6
Departament de Física de la Matèria Condensada, Universitat de Barcelona, Barcelona 08028, Spain; Universitat de Barcelona Institute of Complex Systems (UBICS), Barcelona 08028, Spain.
7
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain; Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid 28049, Spain.
8
Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid 28049, Spain; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona 08036, Spain.
9
Albert Einstein College of Medicine, Bronx, NY 10461, USA.
10
Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona 08908, Spain; Centre for Networked Biomedical Research on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid 28029, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain. Electronic address: araya@cmrb.eu.
11
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain; Department of Molecular and Translational Medicine, University of Brescia, Brescia 25121, Italy. Electronic address: consiglio@ub.edu.

Abstract

Parkinson's disease (PD) is associated with the degeneration of ventral midbrain dopaminergic neurons (vmDAns) and the accumulation of toxic α-synuclein. A non-cell-autonomous contribution, in particular of astrocytes, during PD pathogenesis has been suggested by observational studies, but remains to be experimentally tested. Here, we generated induced pluripotent stem cell-derived astrocytes and neurons from familial mutant LRRK2 G2019S PD patients and healthy individuals. Upon co-culture on top of PD astrocytes, control vmDAns displayed morphological signs of neurodegeneration and abnormal, astrocyte-derived α-synuclein accumulation. Conversely, control astrocytes partially prevented the appearance of disease-related phenotypes in PD vmDAns. We additionally identified dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation in PD astrocytes. Finally, chemical enhancement of CMA protected PD astrocytes and vmDAns via the clearance of α-synuclein accumulation. Our findings unveil a crucial non-cell-autonomous contribution of astrocytes during PD pathogenesis, and open the path to exploring novel therapeutic strategies aimed at blocking the pathogenic cross talk between neurons and glial cells.

KEYWORDS:

CRISPR/Cas9; LRRK2; Parkinson's disease; astrocytes; autophagy; disease modeling; iPSC; neurodegeneration; non-cell-autonomous; α-synuclein

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