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

被引：263

作者：

di Domenico, Angelique ^{[1
,2
]}

Carola, Giulia ^{[1
,2
]}

Calatayud, Cartes ^{[1
,2
,3
]}

Pons-Espinal, Meritxell ^{[1
,2
]}

Pablo Munoz, Juan ^{[4
]}

Richaud-Patin, Yvonne ^{[3
,5
]}

Fernandez-Carasa, Irene ^{[1
,2
]}

Gut, Marta ^{[6
]}

Faella, Armida ^{[1
,2
]}

Parameswaran, Janani ^{[1
,2
]}

Soriano, Jordi ^{[7
,8
]}

Ferrer, Isidro ^{[2
,9
]}

Tolosa, Eduardo ^{[9
,10
]}

Zorzano, Antonio ^{[4
]}

Cuervo, Ana Maria ^{[11
]}

Raya, Angel ^{[3
,5
,12
]}

Consiglio, Antonella ^{[1
,2
,13
]}

机构：

[1] Bellvitge Univ Hosp IDIBELL, Hosp Llobregat, Dept Pathol & Expt Therapeut, Barcelona 08908, Spain

[2] IBUB, Barcelona 08028, Spain

[3] Hosp Llobregat, Hosp Duran I Reynals, Ctr Regenerat Med Barcelona CMRB, Barcelona 08908, Spain

[4] IRB, Carrer Baldiri Reixac 10, Barcelona 08028, Spain

[5] Ctr Networked Biomed Res Bioengn Biomat & Nanomed, Madrid 28029, Spain

[6] CNAG, CRG, Parc Cientif Barcelona, Barcelona 08028, Spain

[7] Univ Barcelona, Dept Fis Mat Condensada, E-08028 Barcelona, Spain

[8] UBICS, Barcelona 08028, Spain

[9] Ctr Networked Biomed Res Neurodegenerat Dis CIBER, Madrid 28049, Spain

[10] UB, Inst Invest Biomed August Pi I Sunyer IDIBAPS, Hosp Clin Barcelona, Dept Neurol, Barcelona 08036, Spain

[11] Albert Einstein Coll Med, Bronx, NY 10461 USA

[12] ICREA, Barcelona 08010, Spain

[13] Univ Brescia, Dept Mol & Translat Med, I-25121 Brescia, Italy

来源：

STEM CELL REPORTS | 2019年 / 12卷 / 02期

基金：

欧洲研究理事会;

关键词：

CHAPERONE-MEDIATED AUTOPHAGY; MUTANT ALPHA-SYNUCLEIN; COMMON LRRK2 MUTATION; DOPAMINE NEURONS; HUMAN ES; PATHOLOGY; DYSFUNCTION; TOXICITY; BLOCKAGE; MODELS;

D O I：

10.1016/j.stemcr.2018.12.011

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Parkinson's disease (PD) is associated with the degeneration of ventral midbrain dopaminergic neurons (vmDAns) and the accumulation of toxic alpha-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 alpha-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 alpha-synuclein accumulation in PD astrocytes. Finally, chemical enhancement of CMA protected PD astrocytes and vmDAns via the clearance of alpha-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.

引用

页码：213 / 229

页数：17

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