Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson's disease

di Domenico, Angelique; Carola, Giulia; Calatayud, Carles; Pons Espinal, Meritxell, 1986-; Muñoz, Juan Pablo; Richaud Patin, Yvonne; Fernández Carasa, Irene; Gut, Marta; Faella, Armida; Parameswaran, Janani, 1990-; Soriano, Jordi; Ferrer, Isidre; Tolosa, Eduard; Zorzano, Antonio; Cuervo, Ana Maria; Raya Chamorro, Ángel; Consiglio, Antonella

Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson's disease

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dc.contributor.author di Domenico, Angelique
dc.contributor.author Carola, Giulia
dc.contributor.author Calatayud, Carles
dc.contributor.author Pons Espinal, Meritxell, 1986-
dc.contributor.author Muñoz, Juan Pablo
dc.contributor.author Richaud Patin, Yvonne
dc.contributor.author Fernández Carasa, Irene
dc.contributor.author Gut, Marta
dc.contributor.author Faella, Armida
dc.contributor.author Parameswaran, Janani, 1990-
dc.contributor.author Soriano, Jordi
dc.contributor.author Ferrer, Isidre
dc.contributor.author Tolosa, Eduard
dc.contributor.author Zorzano, Antonio
dc.contributor.author Cuervo, Ana Maria
dc.contributor.author Raya Chamorro, Ángel
dc.contributor.author Consiglio, Antonella
dc.date.accessioned 2019-03-22T08:07:24Z
dc.date.available 2019-03-22T08:07:24Z
dc.date.issued 2019
dc.description.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.
dc.description.sponsorship We are thankful to Mark Cookson for the LRRK2 G2019S plasmid (Addgene Plasmid No. 29401). We are grateful to the Advanced Fluorescence Microscopy Unit of the Institute of Biomedicine of the University of Barcelona (especially to Elena Rebollo Arredondo). Research from the authors' laboratories is supported by the European Research Council (ERC) (2012-StG-311736-PD-HUMMODEL), the Spanish Ministry of Economy and Competitiveness (MINECO) (FIS2016-78507-C2-2-P, SAF2015-69706-R, and BFU2016-80870-P), Instituto de Salud Carlos III (ISCIII/FEDER) (Red de Terapia Celular [TerCel] RD16/0011/0024), AGAUR (2014-SGR-878 and 2017-SGR-899), and CERCA Program/Generalitat de Catalunya. A.D. is supported by the PD-HUMMODEL ERC-Ideas PhD fellowship. C.C. and G.C. are partially supported by predoctoral fellowships from the Spanish Ministry of Education (MEC) (FPU12/03332) and MINECO (BES-2014-069603), respectively.
dc.format.mimetype application/pdf
dc.identifier.citation di Domenico A, Carola G, Calatayud C, Pons-Espinal M, Muñoz JP, Richaud-Patin Y, Fernandez-Carasa I, Gut M, Faella A, Parameswaran J, Soriano J, Ferrer I, Tolosa E, Zorzano A, Cuervo AM, Raya A, Consiglio A. Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson's disease. Stem Cell Reports. 2019; 12(2):213-229. DOI 10.1016/j.stemcr.2018.12.011
dc.identifier.doi http://dx.doi.org/10.1016/j.stemcr.2018.12.011
dc.identifier.issn 2213-6711
dc.identifier.uri http://hdl.handle.net/10230/36889
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Stem Cell Reports. 2019; 12(2):213-229
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/FIS2016-78507-C2-2-P
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-69706-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-80870-P
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BES-2014-069603
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword iPSC
dc.subject.keyword Parkinson's disease
dc.subject.keyword Non-cell-autonomous
dc.subject.keyword Astrocytes
dc.subject.keyword α-synuclein
dc.subject.keyword LRRK2
dc.subject.keyword CRISPR/Cas9
dc.subject.keyword Disease modeling
dc.subject.keyword Autophagy
dc.subject.keyword Neurodegeneration
dc.title Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson's disease
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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