A team of researchers has used stem cells taken from the skin of patients with Rett syndrome -- the most physically disabling of the autism disorders -- to replicate autism in the lab and to study how the disease affects brain cells. The team's findings, to be published on Nov. 12 in the journal Cell, reveal disease-specific cellular defects, such as fewer functional connections between particular neurons, and demonstrate these defects are reversible. The results raise the hope that, one day, autism may become a treatable condition.
"The beauty and excitement of this new work is the demonstration that we can use patients' skin to study autism," said Gong Chen, associate professor of biology at Penn State and one of the study's authors. Before this research, scientists had been limited to studying the brains of people with autistic-spectrum disorders via imaging technologies or with postmortem brain tissues. "The fully-functional neurons derived from skin are no different in their electrophysiology properties from neurons isolated from the brain. I believe this study, together with other recent studies, will provide hope for patient-specific stem-cell therapy in treating some diseases that currently are difficult to cure."
Rett syndrome primarily affects girls, and the symptoms often become apparent just after they have learned to walk and say a few words. Affected children regress into an infant-like state, losing speech and motor skills, and developing stereotypical movements and autistic characteristics. "Mental disease, and particularly autism, still carry the stigma of bad parenting," said Alysson Muotri, an assistant professor in the Department of Molecular and Cellular Medicine at the University of California, San Diego School of Medicine, and one of the study's authors. "We show very clearly that autism is a biological disease that is caused by a developmental defect directly affecting brain cells."
Because almost all cases of Rett syndrome are caused by a single mutation in the MeCP2 gene, the team took skin biopsies from patients carrying the mutated gene. By exposing the skin cells to four reprogramming factors, they "turned back the clock," triggering the cells to look and act like embryonic stem cells. Known at this point as "induced pluripotent" stem cells, the Rett-derived cells were indistinguishable from their normal counterparts.
It was only after the team had patiently coaxed the stem cells to develop into fully functioning neurons -- a process that can take up to several months -- that they were able to discern differences between the two. Neurons carrying the MeCP2 mutations had smaller cell bodies, a reduced number of synapses and dendritic spines, and electrophysical defects, indicating that things start to go wrong early in development. "It is quite amazing that we can recapitulate a psychiatric disease in a Petri dish," said author Fred Gage, a professor in the Salk Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. "Being able to study Rett neurons in a dish allows us to identify subtle alterations in the function of the neuronal circuitry that we never had access to before."
The team also found that insulin-like growth factor 1 (IGF-1) -- a hormone that has a role in regulating cell growth and neuronal development -- was able to reverse some of the symptoms of Rett syndrome by restoring proper function to Rett neurons grown in culture. In summary, they found that IGF-1 treatment increased the number of synapses and spines, reverting the neurons to a closer-to-normal stage. This finding suggests that autism is not necessarily permanent and could be at least partially reversible. The new research also opens up the prospect of developing a drug treatment for Rett syndrome and other forms of autism. "Rett syndrome is sometimes considered a 'Rosetta Stone' that can help us to understand other developmental neurological disorders since it shares genetic links with other conditions such as autism and schizophrenia," said author Maria Carol Marchetto, a postdoctoral researcher in the Laboratory of Genetics at the Salk Institute.
Along with Chen, Muotri, Gage, and Marchetto, other researchers who contributed to the work include Cassiano Carromeu, Allan Acab, Gene Yeo at the University of California, San Diego; and Diana Yu and Yangling Mu at the Salk Institute for Biological Studies.
This work was supported by the Emerald Foundation Young Investigator Award, the National Institutes of Health through the NIH Director's New Innovator Award Program, the California Institute for Regenerative Medicine, The Lookout Fund, and the Picower Foundation.
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