Browsing by Subject "MENTAL-RETARDATION PROTEIN"

Sort by: Order: Results:

Now showing items 1-2 of 2
  • Danesi, Claudia Elisabetta; Keinänen, Kari Pekka; Castren, Maija Liisa (2019)
    Fragile X syndrome (FXS) is a neurodevelopmental disorder that represents a common cause of intellectual disability and is a variant of autism spectrum disorder (ASD). Studies that have searched for similarities in syndromic and non-syndromic forms of ASD have paid special attention to alterations of maturation and function of glutamatergic synapses. Copy number variations (CNVs) in the loci containing genes encoding alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) subunits are associated with ASD in genetic studies. In FXS, dysregulated AMPAR subunit expression and trafficking affect neural progenitor differentiation and synapse formation and neuronal plasticity in the mature brain. Decreased expression of GluA2, the AMPAR subunit that critically controls Ca2+-permeability, and a concomitant increase in Ca2+-permeable AMPARs (CP-AMPARs) in human and mouse FXS neural progenitors parallels changes in expression of GluA2-targeting microRNAs (miRNAs). Thus, posttranscriptional regulation of GluA2 by miRNAs and subsequent alterations in calcium signaling may contribute to abnormal synaptic function in FXS and, by implication, in some forms of ASD.
  • Utami, Kagistia Hana; Skotte, Nils H.; Colaco, Ana R.; Yusof, Nur Amirah Binte Mohammad; Sim, Bernice; Yeo, Xin Yi; Bae, Han-Gye; Garcia-Miralles, Marta; Radulescu, Carola I.; Chen, Qiyu; Chaldaiopoulou, Georgia; Liany, Herty; Nama, Srikanth; Peteri, Ulla-Kaisa A.; Sampath, Prabha; Castrén, Maija; Jung, Sangyong; Mann, Matthias; Pouladi, Mahmoud (2020)
    BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Efforts to understand the molecular underpinnings of the disease have been largely performed in rodent or nonisogenic settings. A detailed examination of the impact of FMRP loss on cellular processes and neuronal properties in the context of isogenic human neurons remains lacking. METHODS: Using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to introduce indels in exon 3 of FMR1, we generated an isogenic human pluripotent stem cell model of FXS that shows complete loss of FMRP expression. We generated neuronal cultures and performed genome-wide transcriptome and proteome profiling followed by functional validation of key dysregulated processes. We further analyzed neurodevelopmental and neuronal properties, including neurite length and neuronal activity, using multielectrode arrays and patch clamp electrophysiology. RESULTS: We showed that the transcriptome and proteome profiles of isogenic FMRP-deficient neurons demonstrate perturbations in synaptic transmission, neuron differentiation, cell proliferation and ion transmembrane transporter activity pathways, and autism spectrum disorder-associated gene sets. We uncovered key deficits in FMRP-deficient cells demonstrating abnormal neural rosette formation and neural progenitor cell proliferation. We further showed that FMRP-deficient neurons exhibit a number of additional phenotypic abnormalities, including neurite outgrowth and branching deficits and impaired electrophysiological network activity. These FMRP-deficient related impairments have also been validated in additional FXS patient-derived human-induced pluripotent stem cell neural cells. CONCLUSIONS: Using isogenic human pluripotent stem cells as a model to investigate the pathophysiology of FXS in human neurons, we reveal key neural abnormalities arising from the loss of FMRP.