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Sanford-Burnham researchers unravel molecular roots of Down syndrome
LA JOLLA Calif.—With several papers published recently that provide new information about the genetics behind Down syndrome or how to reverse some of its cognitive effects, a team of researchers from the Sanford-Burnham Medical Research Institute are throwing their hats into the ring with a study describing how the extra chromosome inherited in the congenital disorder alters brain and body development.
People with Down syndrome have an extra copy of chromosome 21, leading to an overdosage of the gene products and noncoding RNAs encoded by this chromosome. This manifests as defects in multiple organs and causes developmental delays and learning disabilities.
Substantial dendritic and synaptic abnormalities, including decreased dendritic arborization and a reduction in synaptic number, have been observed in both prenatal and postnatal Down syndrome brains. The balance between excitatory and inhibitory synapses is reportedly impaired in the brains of both humans with Down's syndrome and mouse models of the disease. Impaired long-term potentiation has also been detected in the hippocampal CA1 region of Ts65Dn mice, a widely used Down syndrome mouse model. Although several chromosome 21–encoded products, such as β-amyloid precursor protein (APP), are thought to contribute to the pathology of Down syndrome, the detailed molecular mechanisms remain largely unclear.
As reported in the March 27 edition of ddn Online, scientists from Roche, the University of Cantabria and Spain's Cajal Institute recently published a potential new approach to combat the cognitive damage caused by Down syndrome. Through the use of an investigational compound, RO4938581, the researchers were able to selectively block specific receptors in the brain and reverse neurological deficits in a mouse model of Down syndrome.
In another study making headlines, researchers at Monash University suggest that a common cough syrup ingredient can improve learning and cognitive abilities of people with the genetic disorder.
In this paper, Sanford-Burnham researchers demonstrate a new role for Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, in the dysregulation of synaptic function in Down syndrome. Working with mice that lack one copy of the snx27 gene, the researchers observed that the mice were mostly normal, but showed some significant defects in learning and memory, and that SNX27 helps keep glutamate receptors on the cell surface in neurons.
Because neurons need glutamate receptors in order to function correctly, and these mice had fewer active glutamate receptors, the researchers concluded that less SNX27 causes impaired learning and memory.
"In the brain, SNX27 keeps certain receptors on the cell surface—receptors that are necessary for neurons to fire properly," says Dr. Huaxi Xu, a professor in Sanford-Burnham's Del E. Webb Neuroscience, Aging and Stem Cell Research Center and senior author of the study. "So in Down syndrome, we believe lack of SNX27 is at least partly to blame for developmental and cognitive defects."
Xu and his colleagues then set out to probe how Down syndrome and low SNX27 are connected. They hypothesized that microRNAs, small pieces of genetic material that don't code for protein, influence the production of other genes. They observed that chromosome 21 encodes one particular microRNA called miR-155. In human Down syndrome brains, the increase in miR-155 levels correlates almost perfectly with the decrease in SNX27.
Ultimately, the researchers believe that restoring SNX27 in Down syndrome mice improves cognitive function and behavior.
"Everything goes back to normal after SNX27 treatment. It's amazing—first we see the glutamate receptors come back, then memory deficit is repaired in our Down syndrome mice, " said Xin Wang, a graduate student in Xu's lab and first author of the study. "Gene therapy of this sort hasn't really panned out in humans, however. So we're now screening small molecules to look for some that might increase SNX27 production or function in the brain."
Xu notes that "this is not going to happen overnight. It may take 10 to 15 years, but this is a clear pathway to understanding the underlying pathogenesis of Down syndrome."
"miR-155 could be an early target, but I think a combination of targeting increased SNX27 or a knockdown of miR-155 in combination is the right way to go," he adds.
Xu, whose career is marked by many published works in the field of Alzheimer's disease, adds that "this is my first published work on Down syndrome, but regardless, Alzheimer's disease and Down syndrome share common pathologies and a lot of common mechanisms. "
The study, "Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down syndrome," was supported in part by the Intramural Research Program of the U.S. National Institutes of Health, the National Cancer Institute and the Center for Cancer Research.