Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome
(2021) In GLIA 69(12). p.2947-2962- Abstract
The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes. Levels of uPA were also increased in conditioned medium... (More)
The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes. Levels of uPA were also increased in conditioned medium collected from FXS hiPSC-derived astrocyte cultures and correlated inversely with intracellular Ca2+ responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB within the docking site for the phospholipase-Cγ1 (PLCγ1), indicating effects of uPA on neuronal plasticity. Gene expression changes during neuronal differentiation preceding astrogenesis likely contributed to properties of astrocytes with FXS-specific alterations that showed specificity by not affecting differentiation of adenosine triphosphate (ATP)-responsive astrocyte population. To conclude, our studies identified uPA as an important regulator of astrocyte function and demonstrated that increased uPA in human FXS astrocytes modulated astrocytic responses and neuronal plasticity.
(Less)
- author
- organization
- publishing date
- 2021-08-24
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- astrocyte, fragile X syndrome, neuronal plasticity, urokinase plasminogen activator
- in
- GLIA
- volume
- 69
- issue
- 12
- pages
- 2947 - 2962
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- scopus:85113818425
- pmid:34427356
- ISSN
- 0894-1491
- DOI
- 10.1002/glia.24080
- language
- English
- LU publication?
- yes
- id
- 1d55cb01-cd36-4af2-a642-9f91319d8497
- date added to LUP
- 2021-09-27 13:04:13
- date last changed
- 2024-06-15 16:56:09
@article{1d55cb01-cd36-4af2-a642-9f91319d8497,
abstract = {{<p>The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes. Levels of uPA were also increased in conditioned medium collected from FXS hiPSC-derived astrocyte cultures and correlated inversely with intracellular Ca<sup>2+</sup> responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB within the docking site for the phospholipase-Cγ1 (PLCγ1), indicating effects of uPA on neuronal plasticity. Gene expression changes during neuronal differentiation preceding astrogenesis likely contributed to properties of astrocytes with FXS-specific alterations that showed specificity by not affecting differentiation of adenosine triphosphate (ATP)-responsive astrocyte population. To conclude, our studies identified uPA as an important regulator of astrocyte function and demonstrated that increased uPA in human FXS astrocytes modulated astrocytic responses and neuronal plasticity.</p>}},
author = {{Peteri, Ulla Kaisa and Pitkonen, Juho and de Toma, Ilario and Nieminen, Otso and Utami, Kagistia Hana and Strandin, Tomas M. and Corcoran, Padraic and Roybon, Laurent and Vaheri, Antti and Ethell, Iryna and Casarotto, Plinio and Pouladi, Mahmoud A. and Castrén, Maija L.}},
issn = {{0894-1491}},
keywords = {{astrocyte; fragile X syndrome; neuronal plasticity; urokinase plasminogen activator}},
language = {{eng}},
month = {{08}},
number = {{12}},
pages = {{2947--2962}},
publisher = {{John Wiley & Sons Inc.}},
series = {{GLIA}},
title = {{Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome}},
url = {{http://dx.doi.org/10.1002/glia.24080}},
doi = {{10.1002/glia.24080}},
volume = {{69}},
year = {{2021}},
}