Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease.
Stem Cell Reports
; 12(2): 213-229, 2019 02 12.
Article
em En
| MEDLINE
| ID: mdl-30639209
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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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Astrócitos
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Células-Tronco Pluripotentes Induzidas
Tipo de estudo:
Observational_studies
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Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Stem Cell Reports
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Espanha