Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson's disease

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...

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Detalles Bibliográficos
Autores: di Domenico, Angelique, Carola, Giulia, Calatayud, Carles, Pons Espinal, Meritxell, 1986-, Muñoz, Juan Pablo, Richaud Patin, Yvonne, Fernández Carasa, Irene, Gut, Marta, Faella, Armida, Parameswaran, Janani, 1990-, Soriano, Jordi, Ferrer, Isidre, Tolosa, Eduard, Zorzano, Antonio, Cuervo, Ana Maria, Raya Chamorro, Ángel, Consiglio, Antonella
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/36889
Acceso en línea:http://hdl.handle.net/10230/36889
http://dx.doi.org/10.1016/j.stemcr.2018.12.011
Access Level:acceso abierto
Palabra clave:iPSC
Parkinson&apos
s disease
Non-cell-autonomous
Astrocytes
α-synuclein
LRRK2
CRISPR/Cas9
Disease modeling
Autophagy
Neurodegeneration
Descripción
Sumario: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.

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