Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Autor: Ulla Kaisa Peteri, Juho Pitkonen, Mahmoud A. Pouladi, Antti Vaheri, Laurent Roybon, Maija L. Castrén, Iryna M. Ethell, Plinio C. Casarotto, Kagistia Hana Utami, Tomas Strandin, Otso Nieminen, Pádraic Corcoran, Ilario de Toma
Přispěvatelé: NeuroDevDiseaseModelling, Medicum, Department of Physiology, Department of Virology, Viral Zoonosis Research Unit
Rok vydání: 2021
Předmět:
congenital
hereditary
and neonatal diseases and abnormalities
MIGRATION
Autism Spectrum Disorder
Population
Induced Pluripotent Stem Cells
Tropomyosin receptor kinase B
Biology
3124 Neurology and psychiatry
Extracellular matrix
PATHWAY
03 medical and health sciences
Cellular and Molecular Neuroscience
Mice
0302 clinical medicine
astrocyte
medicine
neuronal plasticity
Animals
Humans
Receptor
education
urokinase plasminogen activator
EPILEPSY
030304 developmental biology
0303 health sciences
education.field_of_study
WNT/BETA-CATENIN
Voltage-dependent calcium channel
RECEPTOR
CENTRAL-NERVOUS-SYSTEM
3112 Neurosciences
MOUSE MODEL
GENE
Urokinase-Type Plasminogen Activator
Cell biology
medicine.anatomical_structure
DIFFERENTIATION
Neurology
Astrocytes
Fragile X Syndrome
Neuron
030217 neurology & neurosurgery
Intracellular
Astrocyte
RESPONSES
Zdroj: GliaREFERENCES. 69(12)
ISSN: 1098-1136
Popis: 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.
Databáze: OpenAIRE
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