Article

A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells

The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell (Impact Factor: 32.24). 11/2010; 143(4):527-39. DOI: 10.1016/j.cell.2010.10.016
Source: PubMed

ABSTRACT

Autism spectrum disorders (ASD) are complex neurodevelopmental diseases in which different combinations of genetic mutations may contribute to the phenotype. Using Rett syndrome (RTT) as an ASD genetic model, we developed a culture system using induced pluripotent stem cells (iPSCs) from RTT patients' fibroblasts. RTT patients' iPSCs are able to undergo X-inactivation and generate functional neurons. Neurons derived from RTT-iPSCs had fewer synapses, reduced spine density, smaller soma size, altered calcium signaling and electrophysiological defects when compared to controls. Our data uncovered early alterations in developing human RTT neurons. Finally, we used RTT neurons to test the effects of drugs in rescuing synaptic defects. Our data provide evidence of an unexplored developmental window, before disease onset, in RTT syndrome where potential therapies could be successfully employed. Our model recapitulates early stages of a human neurodevelopmental disease and represents a promising cellular tool for drug screening, diagnosis and personalized treatment.

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    • "The study of iPSCs derived neurons has emerged as a popular means of modeling disease53545556, but less attention has been given to NPCs. Support for the use of NPCs has come from studies of schizophrenia, bipolar disorder, and Rett Syndrome[13,14,575859. For example, Topol et al. discovered altered WNT signaling in NPCs derived from schizophrenia patients, a pathway previously known to be dysregulated in post-mortem brain of individuals with schizophrenia and thought to be a target of many antipsychotic drugs[60,61]. "
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    ABSTRACT: Deletions encompassing the BP1-2 region at 15q11.2 increase schizophrenia and epilepsy risk, but only some carriers have either disorder. To investigate the role of CYFIP1, a gene within the region, we performed knockdown experiments in human neural progenitors derived from donors with 2 copies of each gene at the BP1-2 locus. RNA-seq and cellular assays determined that knockdown of CYFIP1 compromised cytoskeletal remodeling. FMRP targets and postsynaptic density genes, each implicated in schizophrenia, were significantly overrepresented among differentially expressed genes (DEGs). Schizophrenia and/or epilepsy genes, but not those associated with randomly selected disorders, were likewise significantly overrepresented. Mirroring the variable expressivity seen in deletion carriers, marked between-line differences were observed for dysregulation of disease genes. Finally, a subset of DEGs showed a striking similarity to known epilepsy genes and represents novel disease candidates. Results support a role for CYFIP1 in disease and demonstrate that disease-related biological signatures are apparent prior to neuronal differentiation.
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    • "Dendritic spines form the principal location at which excitatory synaptic transmission and synaptic plasticity takes place and moreover, numerous neurological diseases are accompanied by spine number or size alterations (Bourne & Harris, 2008; Penzes et al., 2011). In this respect it is of significance that in vivo integrated hPSC C neurons do appear to develop spine-like structures (Espuny-Camucho et al., 2013), but dendritic spines structures with co-localised expression of PSD-95 are infrequent in in vitro hPSC-derived neurons (Marchetto et al., 2010). "
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    ABSTRACT: The in vitro derivation of regionally defined human neuron types from patient-derived stem cells is now established as a resource to investigate human development and disease. Characterisation of such neurons initially focused on the expression of developmentally regulated transcription factors and neural markers, in conjunction with the development of protocols to direct and chart the fate of differentiated neurons. However, crucial to the understanding and exploitation of this technology is to determine the degree to which neurons recapitulate the key functional features exhibited by their native counterparts, essential for determining their usefulness in modelling human physiology and disease in vitro. Here, we review the emerging data concerning functional properties of human pluripotent stem cell-derived excitatory cortical neurons, both in the context of maturation and regional specificity. This article is protected by copyright. All rights reserved.
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    • "In particular, modeling neurological diseases is of great interest given that it is difficult to obtain patient-derived neural cells or tissues because of the limited accessibility to the brain. Indeed, ESCs and iPSCs derived from patients have been used to study several neurological diseases, including amyotrophic lateral sclerosis (ALS; Dimos et al., 2008; Egawa et al., 2012), Alzheimer's disease (AD; Israel et al., 2012; Kondo et al., 2013; Yagi et al., 2011), Parkinson's disease (Devine et al., 2011; Imaizumi et al., 2012; Nguyen et al., 2011), schizophrenia (Brennand et al., 2011; Bundo et al., 2014; Hook et al., 2014), epilepsy (Higurashi et al., 2013; Jiao et al., 2013; Liu et al., 2013), and Rett syndrome (Andoh-Noda et al., 2015; Marchetto et al., 2010). Because most neurological diseases affect one or more specific lesion area(s), PSCs were differentiated into corresponding neuronal subtypes in such studies (Imaizumi and Okano, 2014; Marchetto and Gage, 2012; Mattis and Svendsen, 2011; Okano and Yamanaka, 2014). "
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