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Title: Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson's disease
Author: Domenico, Angelique Di
Carola, Giulia
Calatayud Aristoy, Carles
Pons-Espinal, Meritxell
Muñoz, Juan Pablo
Richaud-Patin, Yvonne
Fernandez-Carasa, Irene
Gut, Marta
Faella, Armida
Parameswaran, Janani
Soriano i Fradera, Jordi
Ferrer, Isidro (Ferrer Abizanda)
Tolosa, Eduardo
Zorzano Olarte, Antonio
Cuervo, Ana Maria
Raya Chamorro, Ángel
Consiglio, Antonella
Keywords: Malaltia de Parkinson
Parkinson's disease
Issue Date: 12-Feb-2019
Publisher: Elsevier
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.
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It is part of: Stem Cell Reports, 2019, vol. 12, num. 2, p. 213-229
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ISSN: 2213-6711
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Publicacions de projectes de recerca finançats per la UE

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