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

Angelique di Domenico, Giulia Carola, Carles Calatayud, Meritxell Pons-Espinal, Juan Pablo Muñoz, Yvonne Richaud-Patin, Irene Fernandez-Carasa, Marta Gut, Armida Faella, Janani Parameswaran, Jordi Soriano, Isidro Ferrer, Eduardo Tolosa, Antonio Zorzano, Ana Maria Cuervo, Angel Raya, Antonella Consiglio

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)213-229
Number of pages17
JournalStem Cell Reports
Volume12
Issue number2
DOIs
StatePublished - Feb 12 2019

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Keywords

  • CRISPR/Cas9
  • LRRK2
  • Parkinson's disease
  • astrocytes
  • autophagy
  • disease modeling
  • iPSC
  • neurodegeneration
  • non-cell-autonomous
  • α-synuclein

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

di Domenico, A., Carola, G., Calatayud, C., Pons-Espinal, M., Muñoz, J. P., Richaud-Patin, Y., Fernandez-Carasa, I., Gut, M., Faella, A., Parameswaran, J., Soriano, J., Ferrer, I., Tolosa, E., Zorzano, A., Cuervo, A. M., Raya, A., & Consiglio, A. (2019). Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease. Stem Cell Reports, 12(2), 213-229. https://doi.org/10.1016/j.stemcr.2018.12.011