TY - JOUR
T1 - Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease
AU - di Domenico, Angelique
AU - Carola, Giulia
AU - Calatayud, Carles
AU - Pons-Espinal, Meritxell
AU - Muñoz, Juan Pablo
AU - Richaud-Patin, Yvonne
AU - Fernandez-Carasa, Irene
AU - Gut, Marta
AU - Faella, Armida
AU - Parameswaran, Janani
AU - Soriano, Jordi
AU - Ferrer, Isidro
AU - Tolosa, Eduardo
AU - Zorzano, Antonio
AU - Cuervo, Ana Maria
AU - Raya, Angel
AU - Consiglio, Antonella
N1 - Funding Information:
The authors are indebted to the patients with PD who have participated in this study. The authors thank Chrysanthi Blithikioti for helping with some co-culture experiments and ICC, Neus Bayó-Puxan for her advice on western blotting, Jose Miquel Andres Vaquero (CMRB) for performing flow cytometry analysis, and David Maynar for excellent artwork. We are thankful to Mark Cookson for the LRRK2 G2019S plasmid (Addgene Plasmid No. 29401). We are grateful to the Advanced Fluorescence Microscopy Unit of the Institute of Biomedicine of the University of Barcelona (especially to Elena Rebollo Arredondo). Research from the authors’ laboratories is supported by the European Research Council (ERC) (2012-StG-311736-PD-HUMMODEL), the Spanish Ministry of Economy and Competitiveness (MINECO) (FIS2016-78507-C2-2-P, SAF2015-69706-R, and BFU2016-80870-P), Instituto de Salud Carlos III (ISCIII/FEDER) (Red de Terapia Celular [TerCel] RD16/0011/0024), AGAUR (2014-SGR-878 and 2017-SGR-899), and CERCA Program/Generalitat de Catalunya. A.D. is supported by the PD-HUMMODEL ERC-Ideas PhD fellowship. C.C. and G.C. are partially supported by predoctoral fellowships from the Spanish Ministry of Education (MEC) (FPU12/03332) and MINECO (BES-2014-069603), respectively.
Funding Information:
The authors are indebted to the patients with PD who have participated in this study. The authors thank Chrysanthi Blithikioti for helping with some co-culture experiments and ICC, Neus Bayó-Puxan for her advice on western blotting, Jose Miquel Andres Vaquero (CMRB) for performing flow cytometry analysis, and David Maynar for excellent artwork. We are thankful to Mark Cookson for the LRRK2 G2019S plasmid (Addgene Plasmid No. 29401). We are grateful to the Advanced Fluorescence Microscopy Unit of the Institute of Biomedicine of the University of Barcelona (especially to Elena Rebollo Arredondo). Research from the authors' laboratories is supported by the European Research Council (ERC) (2012-StG-311736-PD-HUMMODEL), the Spanish Ministry of Economy and Competitiveness ( MINECO ) (FIS2016-78507-C2-2-P, SAF2015-69706-R , and BFU2016-80870-P ), Instituto de Salud Carlos III (ISCIII/FEDER) (Red de Terapia Celular [TerCel] RD16/0011/0024 ), AGAUR (2014-SGR-878 and 2017-SGR-899 ), and CERCA Program/Generalitat de Catalunya. A.D. is supported by the PD-HUMMODEL ERC-Ideas PhD fellowship. C.C. and G.C. are partially supported by predoctoral fellowships from the Spanish Ministry of Education (MEC) (FPU12/03332) and MINECO (BES-2014-069603), respectively.
Publisher Copyright:
© 2018 The Authors
PY - 2019/2/12
Y1 - 2019/2/12
N2 - 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.
AB - 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.
KW - CRISPR/Cas9
KW - LRRK2
KW - Parkinson's disease
KW - astrocytes
KW - autophagy
KW - disease modeling
KW - iPSC
KW - neurodegeneration
KW - non-cell-autonomous
KW - α-synuclein
UR - http://www.scopus.com/inward/record.url?scp=85060349694&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060349694&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2018.12.011
DO - 10.1016/j.stemcr.2018.12.011
M3 - Article
C2 - 30639209
AN - SCOPUS:85060349694
SN - 2213-6711
VL - 12
SP - 213
EP - 229
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 2
ER -