Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease | Zendy

Angelique di Domenico | Zendy; Giulia Carola | Zendy; Carles Calatayud | Zendy; Meritxell PonsEspinal | Zendy; Juan Pablo Muñoz | Zendy; Yvonne RichaudPatín | Zendy; Irene FernándezCarasa | Zendy; Marta Gut | Zendy; Armida Faella | Zendy; Janani Parameswaran | Zendy; Jordi Soriano | Zendy; Isidró Ferrer | Zendy; Eduardo Tolosa | Zendy; António Zorzano | Zendy; Ana María Cuervo | Zendy; Ángel Raya | Zendy; Antonella Consiglio | Zendy

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Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease

Author(s) -

Angelique di Domenico,

Giulia Carola,

Carles Calatayud,

Meritxell PonsEspinal,

Juan Pablo Muñoz,

Yvonne RichaudPatín,

Irene FernándezCarasa,

Marta Gut,

Armida Faella,

Janani Parameswaran,

Jordi Soriano,

Isidró Ferrer,

Eduardo Tolosa,

António Zorzano,

Ana María Cuervo,

Ángel Raya,

Antonella Consiglio

Publication year - 2019

Publication title -

stem cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 3.207

H-Index - 76

ISSN - 2213-6711

DOI - 10.1016/j.stemcr.2018.12.011

Subject(s) - neurodegeneration , biology , astrocyte , lrrk2 , parkinson's disease , autophagy , induced pluripotent stem cell , neuroscience , pathogenesis , dopaminergic , substantia nigra , microbiology and biotechnology , disease , dopamine , pathology , central nervous system , immunology , genetics , medicine , embryonic stem cell , apoptosis , gene

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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