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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 Astròcits Autofàgia Alfa-sinucleïna Parkinson's disease Astrocytes Autophagy Alpha-synuclein |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1016/j.stemcr.2018.12.011 |
It is part of: | Stem Cell Reports, 2019, vol. 12, num. 2, p. 213-229 |
URI: | http://hdl.handle.net/2445/141851 |
Related resource: | https://doi.org/10.1016/j.stemcr.2018.12.011 |
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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