Domenico, Angelique DiCarola, GiuliaCalatayud Aristoy, CarlesPons-Espinal, MeritxellMuñoz, Juan PabloRichaud-Patin, YvonneFernandez-Carasa, IreneGut, MartaFaella, ArmidaParameswaran, JananiSoriano i Fradera, JordiFerrer, Isidro (Ferrer Abizanda)Tolosa, EduardoZorzano Olarte, AntonioCuervo, Ana MariaRaya Chamorro, ÁngelConsiglio, Antonella2019-10-082019-10-082019-02-122213-6711https://hdl.handle.net/2445/141851Parkinson'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.17 p.application/pdfengcc-by (c) Domenico, Angelique Di et al., 2019http://creativecommons.org/licenses/by/3.0/esMalaltia de ParkinsonAstròcitsAutofàgiaAlfa-sinucleïnaParkinson's diseaseAstrocytesAutophagyAlpha-synucleininfo:eu-repo/semantics/article6875412019-10-08info:eu-repo/semantics/openAccess30639209