New genetic cause for learning disability in Down syndrome identitfied

Neurons from a normal mouse (left) are longer and fuller than neurons from a mouse lacking SNX27 (right).

By Dr. Leila Luheshi from PHG Foundation:

Researchers have reported a novel molecular mechanism through which triplication of chromosome 21 could cause deficits in learning and memory in patients with Down syndrome.
Down syndrome is caused by the abnormal inheritance of three (rather than the usual two) copies of chromosome 21.  At a genetic level this leads to higher than normal levels of expression of the many genes and non-coding RNAs that are encoded on this chromosome.  Clinically this results in a complex constellation of symptoms of which the most prominent is a varying degree of learning disability.  Learning disability in Down syndrome is associated with reductions in the number and activity of the synapses (connections) made between neurons in the brain, and so understanding the mechanisms underlying these neurodevelopmental abnormalities may provide the key to ameliorating the effects of this disorder.

A new study in Nature Medicine reports that the protein encoded by the sorting nexin 27 (SNX27) gene, which is present at abnormally low levels in the brain of patients with Down syndrome, may underlie the presence of learning disabilities in this condition. 

The researchers showed, by knocking out the Snx27 gene in mice, that its expression is vital for brain development.  In particular they discovered that Snx27 is vital for the maintenance of synaptic activity and consequently for learning and memory, deficits in which underlie learning disability in patients with Down syndrome.  In a key experiment that linked these observations in mice more directly with the symptoms of Down syndrome in humans, the team were able to demonstrate that increasing Snx27 levels in a mouse model of Down syndrome could reverse the learning and memory deficits from which it is suffers.  

Molecular Roots of Down Syndrome Unraveled

Neurons from a typical mouse (left) are longer and fuller than neurons from a mouse lacking SNX27 (right). (Credit: Image courtesy of Sanford-Burnham Medical Research Institute)

from Science Daily:
Researchers have discovered that the extra chromosome inherited in Down syndrome impairs learning and memory because it leads to low levels of SNX27 protein in the brain.
What is it about the extra chromosome inherited in Down syndrome -- chromosome 21 -- that alters brain and body development? Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) have new evidence that points to a protein called sorting nexin 27, or SNX27. SNX27 production is inhibited by a molecule encoded on chromosome 21. The study, published March 24 in Nature Medicine, shows that SNX27 is reduced in human Down syndrome brains. The extra copy of chromosome 21 means a person with Down syndrome produces less SNX27 protein, which in turn disrupts brain function. What's more, 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 -- receptors that are necessary for neurons to fire properly," 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."

SNX27's role in brain function
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.