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

Astrocytes / cytology Autophagy / physiology Cell Differentiation / physiology Cells, Cultured Coculture Techniques / methods Dopaminergic Neurons / cytology Humans Induced Pluripotent Stem Cells / cytology Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism Mesencephalon / cytology Neuroglia Parkinson Disease / metabolism Phenotype alpha-Synuclein / metabolism
CRISPR/Cas9 LRRK2 Parkinson's disease astrocytes autophagy disease modeling iPSC neurodegeneration non-cell-autonomous α-synuclein

Journal

Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300

Informations de publication

Date de publication:
12 02 2019
Historique:
received: 07 04 2018
revised: 11 12 2018
accepted: 13 12 2018
pubmed: 15 1 2019
medline: 5 3 2020
entrez: 15 1 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.stemcr.2018.12.011 PMID: 30639209 PMC: PMC6372974
pubmed: 30639209
pii: S2213-6711(18)30530-7
doi: 10.1016/j.stemcr.2018.12.011
pmc: PMC6372974
pii:
doi:

Substances chimiques

alpha-Synuclein 0
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 EC 2.7.11.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

213-229

Subventions

Organisme : NIA NIH HHS
ID : P01 AG031782
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG038072
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG054108
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS100717
Pays : United States

Informations de copyright

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

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Auteurs

Angelique di Domenico (A)

Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain.

Giulia Carola (G)

Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain.

Carles Calatayud (C)

Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain; Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona 08908, Spain.

Meritxell Pons-Espinal (M)

Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain.

Juan Pablo Muñoz (JP)

Institute for Research in Biomedicine (IRB), Carrer Baldiri Reixac 10, Barcelona 08028, Spain.

Yvonne Richaud-Patin (Y)

Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona 08908, Spain; Centre for Networked Biomedical Research on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid 28029, Spain.

Irene Fernandez-Carasa (I)

Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain.

Marta Gut (M)

Centre Nacional d'Anàlisi Genòmica (CNAG-CRG), Parc Científic de Barcelona, Barcelona 08028, Spain.

Armida Faella (A)

Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain.

Janani Parameswaran (J)

Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain.

Jordi Soriano (J)

Departament de Física de la Matèria Condensada, Universitat de Barcelona, Barcelona 08028, Spain; Universitat de Barcelona Institute of Complex Systems (UBICS), Barcelona 08028, Spain.

Isidro Ferrer (I)

Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain; Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid 28049, Spain.

Eduardo Tolosa (E)

Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid 28049, Spain; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona 08036, Spain.

Antonio Zorzano (A)

Institute for Research in Biomedicine (IRB), Carrer Baldiri Reixac 10, Barcelona 08028, Spain.

Ana Maria Cuervo (AM)

Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Angel Raya (A)

Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona 08908, Spain; Centre for Networked Biomedical Research on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid 28029, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain. Electronic address: araya@cmrb.eu.

Antonella Consiglio (A)

Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain; Department of Molecular and Translational Medicine, University of Brescia, Brescia 25121, Italy. Electronic address: consiglio@ub.edu.

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Classifications MeSH

questionsmedicales.fr › Cellules › Névroglie › Astrocytes › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Autophagie › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Cellules › Cellules cultivées › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Techniques d'investigation › Techniques in vitro › Techniques de culture › Techniques de coculture › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Cellules › Neurones › Neurones dopaminergiques › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à la maladie de Parkinson › Leucine-rich repeat serine-threonine protein kinase-2 › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Tronc cérébral › Mésencéphale › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Cellules › Névroglie › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Maladie de Parkinson › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Patient-Specific iPSC-Derived Astrocytes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à la maladie de Parkinson › alpha-Synucléine › Patient-Specific iPSC-Derived Astrocytes...