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Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease
Open accessAbstract
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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“in contrast to neuron-specific cell autonomous mechanisms that affect individual DA neurons within the SNc, non-cell autonomous mechanisms can cause dysfunction across the entire SNc, thereby leading to rapid DA neurodegeneration”
From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as di Domenico et al. 2019
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“Interestingly, astrocytes generated from hiPSC derived from fibroblasts obtained from patients with CNS diseases (usually with a genetic mutation causative of disease or a risk polymorphism) show pathological phenotypes, including dysregulation of lipid metabolism11, alteration in the contents of the extracellular vesicles released by astrocytes80, reduced autophagy81, or altered STAT3 signaling82”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [81]
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Metadata
- Authors
- 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.
- Affiliations
- Bellvitge University Hospital (ES)
- Institute for Research in Biomedicine (ES)
- Centro Nacional de Análisis Genómico (ES)
- Universitat de Barcelona (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Corresponding author
- Consiglio, Antonella
- ORCID
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 12
- Issue
- 2
- Pages
- 213-229
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC6372974
- OpenAlex
- W2911036111
- Cited by
- 372
- References
- 49
- Citations by year
- 2026: 32 · 2025: 38 · 2024: 44 · 2023: 45 · 2022: 65 · 2021: 69 · 2020: 53 · 2019: 26
- FWCI
- 36.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
- Funders
- Agència de Gestió d'Ajuts Universitaris i de Recerca (2014-SGR-878, 2017-SGR-899)
- Ministerio de Educación, Cultura y Deporte (BES-2014-069603, FPU12/03332)
- Ministerio de Economía y Competitividad (BFU2016-80870-P, FIS2016-78507-C2-2-P, SAF2015-69706-R)
- Instituto de Salud Carlos III
- European Regional Development Fund (RD16/0011/0024)
- Generalitat de Catalunya
- European Research Council (2012-StG-311736-PD-HUMMODEL)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Parkinson's disease, astrocytes, non-cell autonomous neurodegeneration, induced pluripotent stem cell-derived astrocytes, dopaminergic neurons, ventral midbrain, LRRK2 G2019S, familial Parkinson's disease, alpha-synuclein accumulation, chaperone-mediated autophagy, macroautophagy, neuron-glia interactions
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Astrocytes, Autophagy, Cell Differentiation, Cells, Cultured, Humans, Mesencephalon, Neuroglia, Parkinson Disease, Phenotype, Coculture Techniques, alpha-Synuclein, Induced Pluripotent Stem Cells, Dopaminergic Neurons
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