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2019-02-12

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cc-by (c) Domenico, Angelique Di et al., 2019
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/141851

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

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https://doi.org/10.1016/j.stemcr.2018.12.011

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.

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Malaltia de Parkinson, Astròcits, Autofàgia, Alfa-sinucleïna

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Parkinson's disease, Astrocytes, Autophagy, Alpha-synuclein

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Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
Publicacions de projectes de recerca finançats per la UE

Citation

DOMENICO, Angelique Di, et al. Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson's disease. Stem Cell Reports. 2019. Vol. 12, num. 2, pags. 213-229. ISSN 2213-6711. [consulted: 6 of June of 2026]. Available at: https://hdl.handle.net/2445/141851

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