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 - 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 -