A collaborative effort between researchers at the Salk Institute for Biological Studies and the University of California, San Diego, successfully used human induced pluripotent stem (iPS) cells derived from patients with Rett syndrome to replicate autism in the lab and study the molecular pathogenesis of the disease.
Their findings, published in the November 12, 2010, issue of Cell, revealed disease-specific cellular defects, such as fewer functional connections between Rett neurons, and demonstrated that these symptoms are reversible, raising the hope that, one day, autism maybe turn into a treatable condition.
Rett syndrome is the most physically disabling of the autism spectrum disorders. Primarily affecting girls, the symptoms of Rett syndrome often become apparent just after they have learned to walk and say a few words. Then, the seemingly normal development slows down and eventually the infants regress, loosing speech and motor skills, developing stereotypical movements and autistic characteristics.
Almost all cases of the disease are caused by a single mutation in the MeCP2 gene, which is involved in the regulation of global gene expression, leading to a host of symptoms that can vary widely in their severity.
Carol Marchetto, Ph.D., a postdoctoral researcher in the Laboratory of Genetics at the Salk Institute, started with skin biopsies taken from four patients carrying four different mutations in the MeCP2 gene and a healthy control. By exposing the skin cells to four reprogramming factors, she 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 she had patiently coaxed the iPS cells to develop into fully functioning neurons -- a process that can take up to several months -- that she was able to discern differences between the two. Neurons carrying the MeCP2 mutations had smaller cell bodies, a reduced number of synapses and dendritic spines, specialized structures that enable cell-cell communication, as well as electrophysical defects, indicating that things start to go wrong early in development.
Since insulin-like growth factor 1 (IGF-1) - a hormone which, among other things, has a role in regulating cell growth and neuronal development - was able to reverse some of the symptoms of Rett syndrome in a mouse model of disease, the Salk researchers tested whether IGF-1 could restore proper function to human Rett neurons grown in culture.
"IGF-1 treatment increased the number of synapses and spines reverting the neuronal phenotype closer to normal," says Fred Gage, Ph.D., a professor in the Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. "This suggests that the autistic phenotype is not permanent and could be, at least partially, reversible."
Researchers who also contributed to the work include Cassiano Carromeu and Allan Acab in the Department of Pediatrics/Cellular & Molecular Medicine at the University of California, San Diego, Diana Yu and Yangling Mu in the Laboratory of Genetics at the Salk Institute for Biological Studies, Gene Yeo in the School of Medicine at the University of California, San Diego, as well as Gong Chen in the Department of Biology at the Pennsylvania State University.
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
Comments