Rett Syndrome

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

Source: 
Cell, Marchetto et al
Date Published: 
November 2010
Year Published: 
2010

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 recapitulate early stages of a human neurodevelopmental disease, using induced pluripotent stem cells (iPSCs) from RTT patients' fibroblasts, which essentially creates a "disease in a dish". The data uncovered early alterations in developing human RTT neurons and suggest evidence of an unexplored developmental window, before disease onset, in RTT syndrome where potential therapies could be successfully employed. Our model represents a promising cellular tool for drug screening, diagnosis and personalized treatment.

Preventing Life Threatening Breathing Disorder of Rett Syndrome

Source: 
Medical News Today
Date Published: 
October 5, 2010
Abstract: 

A group of researchers at the University of Bristol have sequestered the potentially fatal breath holding episodes associated with the autistic-spectrum disorder Rett syndrome. Using a unique combination of drugs, they have discovered that the area of the brain that allows breathing to persist throughout life without interruption has reduced levels of a transmitter substance called aminobutyric acid.

Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Source: 
PNAS, Sur, Tropea, Giacometti, et al.
Date Published: 
February 2009
Year Published: 
2009

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. Here we show that systemic treatment of MeCP2 mutant mice with an active peptide fragment of Insulin-like Growth Factor 1 (IGF-1) extends the life span of the mice, improves locomotor function, ameliorates breathing patterns, and reduces irregularity in heart rate. In addition, treatment with IGF-1 peptide increases brain weight of the mutant mice. Multiple measurements support the hypothesis that RTT results from a deficit in synaptic maturation in the brain: MeCP2 mutant mice have sparse dendritic spines and reduced PSD-95 in motor cortex pyramidal neurons, reduced synaptic amplitude in the same neurons, and protracted cortical plasticity in vivo. Treatment with IGF-1 peptide partially restores spine density and synaptic amplitude, increases PSD-95, and stabilizes cortical plasticity to wild-type levels. Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation.

MeCP2, A Key Contributor to Neurological Disease, Activates and Represses Transcription

Source: 
Science, Chahrour, Jung et al
Date Published: 
2008

Mutations in the gene encoding the transcriptional repressor methyl-CpG binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome. Loss of function as well as increased dosage of the MECP2 gene cause a host of neuropsychiatric disorders. To explore the molecular mechanism(s) underlying these disorders, we examined gene expression patterns in the hypothalamus of mice that either lack or overexpress MeCP2. In both models, MeCP2 dysfunction induced changes in the expression levels of thousands of genes, but unexpectedly the majority of genes (approximately 85%) appeared to be activated by MeCP2. We selected six genes and confirmed that MeCP2 binds to their promoters. Furthermore, we showed that MeCP2 associates with the transcriptional activator CREB1 at the promoter of an activated target but not a repressed target. These studies suggest that MeCP2 regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and a repressor of transcription.