Sanford-Burnham researchers unravel molecular roots of Down syndrome
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
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People with Down syndrome have an extra copy of chromosome21, leading to an overdosage of the gene products and noncoding RNAs encoded bythis chromosome. This manifests as defects in multiple organs and causesdevelopmental delays and learning disabilities.
Substantial dendritic and synaptic abnormalities, includingdecreased dendritic arborization and a reduction in synaptic number, have beenobserved in both prenatal and postnatal Down syndrome brains. The balancebetween excitatory and inhibitory synapses is reportedly impaired in the brainsof both humans with Down's syndrome and mouse models of the disease. Impairedlong-term potentiation has also been detected in the hippocampal CA1 region ofTs65Dn mice, a widely used Down syndrome mouse model. Although several chromosome21–encoded products, such as β-amyloid precursor protein (APP), are thought tocontribute to the pathology of Down syndrome, the detailed molecular mechanismsremain largely unclear.
As reported in the March 27 edition of ddn Online, scientists from Roche, the University of Cantabria andSpain's Cajal Institute recently published a potential new approach to combatthe cognitive damage caused by Down syndrome. Through the use of aninvestigational compound, RO4938581, the researchers were able to selectivelyblock specific receptors in the brain and reverse neurological deficits in amouse model of Down syndrome.
In another study making headlines, researchers at MonashUniversity suggest that a common cough syrup ingredient can improve learningand cognitive abilities of people with the genetic disorder.
In this paper, Sanford-Burnham researchers demonstrate a newrole for Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, in thedysregulation of synaptic function in Down syndrome. Working with mice thatlack one copy of the snx27 gene, the researchers observed that the mice weremostly normal, but showed some significant defects in learning and memory, andthat SNX27 helps keep glutamate receptors on the cell surface in neurons.
Because neurons need glutamate receptors in order tofunction correctly, and these mice had fewer active glutamate receptors, theresearchers concluded that less SNX27 causes impaired learning and memory.
"In the brain, SNX27 keeps certain receptors on the cellsurface—receptors that are necessary for neurons to fire properly," says Dr.Huaxi Xu, a professor in Sanford-Burnham's Del E. Webb Neuroscience, Aging andStem 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 andcognitive defects."
Xu and his colleagues then set out to probe how Downsyndrome and low SNX27 are connected. They hypothesized that microRNAs, smallpieces of genetic material that don't code for protein, influence theproduction of other genes. They observed that chromosome 21 encodes oneparticular microRNA called miR-155. In human Down syndrome brains, the increasein miR-155 levels correlates almost perfectly with the decrease in SNX27.
Ultimately, the researchers believe that restoring SNX27 inDown syndrome mice improves cognitive function and behavior.
"Everything goes back to normal after SNX27 treatment. It'samazing—first we see the glutamate receptors come back, then memory deficit isrepaired in our Down syndrome mice," said Xin Wang, a graduate student in Xu'slab and first author of the study. "Gene therapy of this sort hasn't reallypanned out in humans, however. So we're now screening small molecules to lookfor some that might increase SNX27 production or function in the brain."
Xu notes that "this is not going to happen overnight. It maytake 10 to 15 years, but this is a clear pathway to understanding theunderlying pathogenesis of Down syndrome."
"miR-155 could be an early target, but I think a combinationof targeting increased SNX27 or a knockdown of miR-155 in combination is theright way to go," he adds.
Xu, whose career is marked by many published works in thefield of Alzheimer's disease, adds that "this is my first published work onDown syndrome, but regardless, Alzheimer's disease and Down syndrome sharecommon pathologies and a lot of common mechanisms."
The study, "Loss of sorting nexin 27 contributes toexcitatory synaptic dysfunction by modulating glutamate receptor recycling inDown syndrome," was supported in part by the Intramural Research Program of theU.S. National Institutes of Health, the National Cancer Institute and the Centerfor Cancer Research.
