Título:
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Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson's disease
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Autor/a:
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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
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Notas:
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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. |
Materia(s):
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-Malaltia de Parkinson -Astròcits -Autofàgia -Alfa-sinucleïna -Parkinson's disease -Astrocytes -Autophagy -Alpha-synuclein |
Derechos:
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cc-by (c) Domenico, Angelique Di et al., 2019
http://creativecommons.org/licenses/by/3.0/es
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Tipo de documento:
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Artículo Artículo - Versión publicada |
Editor:
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Elsevier
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Compartir:
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