Molecular Mechanisms Involved in Altered Differentiation of Neural Progenitors in Fragile X Syndrome

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Title: Molecular Mechanisms Involved in Altered Differentiation of Neural Progenitors in Fragile X Syndrome
Author: Achuta, Venkat Swaroop
Contributor: University of Helsinki, Faculty of Medicine, Medicum, Faculty of Medicine, Department of Physiology
Thesis level: Doctoral dissertation (article-based)
Abstract: Fragile X syndrome (FXS) is the most common cause of genetically acquired intellectual disability and is strongly associated with autism spectrum disorders. FXS is an X-linked neurodevelopmental disorder, with an incidence of approximately 1 in 5000 males and 1 in 8000 females. It is primarily caused by a trinucleotide repeat expansion in the Fragile X mental retardation 1 (FMR1) gene leading to epigenetic silencing and loss of FMR1 protein (FMRP). Studies using Fmr1-knockout (Fmr1-KO) mice, modelling FXS, revealed that alterations in glutamatergic signaling play a central role in the aberrances of developmental processes in FXS brain. Tissue plasminogen activator (tPA) is a serine protease that potentiates signaling mediated by glutamate receptors. This thesis explored the effects of tPA and glutamate receptor signaling during early differentiation of FXS neural progenitor cells (NPCs). The differentiation of human and mouse FXS NPCs was characterized using calcium imaging, live cell imaging and immunostaining. Expression of tPA was increased in NPCs and brain of Fmr1-KO mice. The increased tPA was involved in altered neuronal migration and activity-dependent changes in FMRP-deficient mouse NPCs. NPCs were functionally characterized based on their responses to activation of type 1 metabotropic and ionotropic glutamate receptors. Increased differentiation of subpopulations of glutamate-responsive cells was observed in FXS NPCs. Treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), rescued abnormal differentiation of glutamate-responsive cells in both human and mouse FXS NPCs. In addition, MPEP treatment corrected morphological defects and migration of Fmr1-KO cells. Finally, an increased differentiation was evident for cells expressing calcium-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in FXS NPCs and reduced GluA2 expression resulted in increased calcium permeability of AMPA receptors. In summary, this study provides insight into the molecular mechanisms involved in early aberrant differentiation of FXS neuronal cells and will pave the way to develop new therapeutic approaches and biomarkers for FXS.N/A
URI: URN:ISBN:978-951-51-4100-2
Date: 2018-02-27
Rights: This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.

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