di Domenico, AngeliqueCarola, GiuliaCalatayud, CarlesPons Espinal, Meritxell, 1986-Muñoz, Juan PabloRichaud Patin, YvonneFernández Carasa, IreneGut, MartaFaella, ArmidaParameswaran, Janani, 1990-Soriano, JordiFerrer, IsidreTolosa, EduardZorzano, AntonioCuervo, Ana MariaRaya Chamorro, ÁngelConsiglio, Antonella2019-03-222019-03-222019di 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.2018.12.0112213-6711http://hdl.handle.net/10230/36889Parkinson'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.application/pdfeng© 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.stemcr.2018.12.011iPSCParkinson's diseaseNon-cell-autonomousAstrocytesα-synucleinLRRK2CRISPR/Cas9Disease modelingAutophagyNeurodegenerationinfo:eu-repo/semantics/openAccess