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


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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Available from: Cassiano Carromeu
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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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    • "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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    • "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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