Published in November 12, 2010 issue of Cell, Muotri et al. report evidence of a promising cellular tool for drug screening, diagnosis, and personalized treatment for Rett Syndrome, a type of autistic disorder.
Senior author of the paper, Alysson R. Muotri, PhD Assistant Professor at UC San Diego’s Department of Pediatrics and Cellular and Molecular Medicine, hopes the research helps to reduce the stigma attached to this type of psychiatric disease.
“The work presents evidence of a clear genetic autonomous component behind the syndrome,” Muotri says.
Autism spectrum disorders are complex neurodevelopmental diseases affecting 1 in 150 children in the United States. These disorders are mainly characterized by impaired social interaction and repetitive behavior. Family history and twin studies suggest that, in some cases, these disorders share genetic roots, but the degree to which environmental and genetic patterns account for individual differences within autism disorders is currently unknown. A different combination of genetic mutations is likely to play a role in each individual. Nevertheless, the study of mutations in specific genes can help to identify molecular mechanisms responsible for subtle alterations in the nervous system, perhaps pointing to common mechanisms for autism.
Rett syndrome (RTT) is a progressive neurological disorder caused by mutations in the X-linked gene encoding MeCP2 protein. RTT patients have a large spectrum of autistic characteristics and are considered part of the ASD population, and undergo apparently normal development until 6-18 months of age, followed by impaired motor function, stagnation and then regression of developmental skills, hypotonia, seizures and autistic behavior.
Using RTT as an autistic genetic prototype, the study was based on a culture system that was developed using induced pluripotent stem cells (iPSCs). During this procedure, skin cells from patients were reverted or reprogrammed to a more immature pluripotent state, similar to embryonic stem cells. The iPSCs of RTT patients and non-affected controls were able to generate functional neurons. Muotri et al. found that the neurons derived from RTT-iPSCs had fewer synapses, a reduced spine density, a smaller soma size, altered calcium signaling, and electrophysiological defects when compared to neurons derived from healthy normal people. This demonstrated that the researchers were actually able recapitulate the disease in several aspects in the lab, from neuronal morphology to network imbalances.
“Modeling psychiatric diseases is a real challenge. The information gained from postmortem brain tissues was limited to the terminal stage of the disease and animal models not always recapitulate the human condition," Muotri explains. "Now, for the first time, we have the chance to peep inside the cells and understand how the disease develop in human neurons."
Presented data revealed early alterations in developing human RTT neurons – giving the researchers the green light to test the effects of drugs in rescuing synaptic defects. This contributed to an even more significant discovery – using iPSC technology, they were able to revert the ‘disease neurons’ back to normal, providing further evidence that the autistic phenotype is not permanent.
“This is a proof-of-principle for a future drug-screening platform,” Muotri remarks. “Our model nicely recapitulates early stages of a human neurodevelopmental disease and represents a promising methodology for drug screening, diagnosis and personalized treatment.”
While treating autistic disorders after they have developed in the brain may be a herculean task, this novel approach addresses an unexplored developmental window - before disease onset - where potential therapies could be successfully employed.
“This is a very exciting time, where stem cell technologies are revealing the opportunity for novel translational moves,” Muotri says.
The work was supported by the NIH Director’s New Innovator Award and the Emerald Foundation Young Investigator Award to Dr. Muotri. Colleagues from the Salk Institute also contributed to this research.
Scientific Contact: Alysson R. Muotri, PhD Assistant Professor, Department of Pediatrics, UC San Diego School of Medicine/Rady Children's Hospital, Dept. Cellular & Molecular Medicine, and UC San Diego Stem Cell Program email@example.com
IMAGE courtesy of Muotri Lab. Human Pluripotent Cells. Copyright 2010. UC Regents.
Article written by Shivani Singh, Sr. Writer, Dept of Pediatrics, UC San Diego, Rady Children’s Hospital-San Diego, firstname.lastname@example.org