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Title: Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome
Authors: Peteri, Ulla-Kaisa
Pitkonen, Juho
de Toma, Ilario
Nieminen, Otso
Utami, Kagistia Hana 
Strandin, Tomas M.
Corcoran, Padraic
Roybon, Laurent
Vaheri, Antti
Ethell, Iryna
Casarotto, Plinio
Pouladi, Mahmoud A. 
Castrén, M.L.
Keywords: astrocyte
fragile X syndrome
neuronal plasticity
urokinase plasminogen activator
Issue Date: 24-Aug-2021
Publisher: John Wiley and Sons Inc
Citation: Peteri, Ulla-Kaisa, Pitkonen, Juho, de Toma, Ilario, Nieminen, Otso, Utami, Kagistia Hana, Strandin, Tomas M., Corcoran, Padraic, Roybon, Laurent, Vaheri, Antti, Ethell, Iryna, Casarotto, Plinio, Pouladi, Mahmoud A., Castrén, M.L. (2021-08-24). Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome. GLIA 69 (12) : 2947-2962. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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 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-C?1 (PLC?1), 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. © 2021 The Authors. GLIA published by Wiley Periodicals LLC.
Source Title: GLIA
ISSN: 0894-1491
DOI: 10.1002/glia.24080
Rights: Attribution 4.0 International
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