A model for neural development and treatment of Rett Syndrome using human induced pluripotent stem cells
By M. Marchetto, C. Carromeu, Allan Acab, Diana Yu, Gene W. Yeo, Yangling Mu, Gong Chen, Fred H. Gage, Alysson Renato Muotri. Cell, 2010
1,326 citations recorded by the source corpus.
Summary 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.
Subfields: Cognitive Neuroscience, Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/75ce73b003b915696698665f103fa1a595ecfc1a
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Citations in the corpus
- Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. (2012, background): “The culprit gene in 15q11-13 is the ubiquitin E3 ligase ( UBE3A ) (Kishino et al. 1997; Matsuura et al. 1997).”
- Origin and differentiation of microglia (2013, background): “Thus far, efforts to recapitulate neurological disease features in vitro from human iPSCs have mainly focused on the afflicted neurons (Dimos et al., 2008; Park et al., 2008b; Lee et al., 2009; Soldner et al., 2009; Marchetto et al., 2010).”
- All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins (2014, background): “These include Rett syndrome 45 , fragile X 46 , and Phelan-McDermid syndrome 36 .”
- Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations (2011, neutral): “However, so far, only a few such studies have identified disease-related phenotypes, mostly in rare, early age onset or metabolic diseases (Brennand et al., 2011; Ebert et al., 2009; Itzhaki et al., 2011; Lee et al., 2009; Marchetto et al., 2010; Rashid et al., 2010).”