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Mar 25, 2013

Molecular Roots of Down Syndrome Unraveled

  • Scientists at the Sanford-Burnham Medical Research Institute think they found one of the main reasons for explaining how the extra chromosome 21 in Down syndrome patients alters brain and body development.

    The reported new evidence regarding a protein called sorting nexin 27, or SNX2, which is inhibited by a molecule encoded on chromosome 21. Their study, published March 24 in Nature Medicine, shows that SNX27 is reduced in human Down syndrome brains which, in turn, disrupts brain function. In addition, the researchers showed that restoring SNX27 in Down syndrome mice improves cognitive function and behavior.

    “In the brain, SNX27 keeps certain receptors on the cell surface,” said Huaxi Xu, Ph.D., 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.”

    Dr. Xu and colleagues started out working with mice that lack one copy of the snx27 gene. They noticed that the mice were mostly normal, but showed some significant defects in learning and memory. So the team dug deeper to determine why SNX27 would have that effect. They found that SNX27 helps keep glutamate receptors on the cell surface in neurons. Neurons need glutamate receptors in order to function correctly.

    With less SNX27, these mice had fewer active glutamate receptors and thus impaired learning and memory.

    The researchers then began thinking about Down syndrome. The SNX27-deficient mice shared some characteristics with Down syndrome, so they took a look at human brains with the condition. This confirmed the clinical significance of their laboratory findings: humans with Down syndrome have significantly lower levels of SNX27.

    Dr. Xu and his colleagues wondered how Down syndrome and low SNX27 are connected. Could the extra chromosome 21 encode something that affects SNX27 levels? They suspected microRNAs, which don’t code for protein, but do influence the production of other genes. It turns out 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, according to Dr. Xu who, along with his team concluded that, due to the extra chromosome 21 copy, the brains of people with Down syndrome produce extra miR-155, which by indirect means decreases SNX27 levels, in turn decreasing surface glutamate receptors. Through this mechanism, learning, memory, and behavior are impaired.

    The real interesting question is, if people with Down syndrome simply have too much miR-155 or not enough SNX27, could that be fixed? The team explored this possibility. They used a noninfectious virus as a delivery vehicle to introduce new human SNX27 in the brains of Down syndrome mice.

    “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,” noted Xin Wang, a graduate student in Dr. 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.”

    According to the National Down Syndrome Society, one in every 691 children in the U.S. is born with Down syndrome. There are more than 400,000 people living with Down syndrome in the U.S.


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