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Brain protein may play role in Down's syndrome

Monday 25 March 2013

BBC News reports that low levels of a particular protein may contribute to some of the characteristics of Down's syndrome. The news comes from a study that builds on previous research into the condition, which found abnormalities in the connections between nerve cells in the brains of people with Down's syndrome.

In this study, mice were genetically engineered to lack the protein (SNX27) involved in this nerve cell connection. The researchers found that mice lacking the protein were less able to learn and memorise how to navigate a maze.

Further examination of their brains showed that a lack of the protein led to a loss of certain chemical (glutamate) receptors involved in nerve cell connections. These connections were in areas of the brain thought to play an important role in learning and memory.

Similar examination of brain samples taken from people with Down's syndrome revealed that they also had reduced amounts of the SNX27 protein and a loss of glutamate receptors.

This research offers possible new insights into how chemical signalling between nerve cells may function in people with Down's syndrome, but it has no current implications for the treatment or prevention of the condition.

Where did the story come from?

The study was carried out by researchers from Sanford-Burnham Medical Research Institute, La Jolla, California, and other research institutions in the USA, China and Malaysia. The research received financial support from various sources, including the US National Institutes of Health.

It was published in the peer-reviewed journal Nature Medicine.

BBC News provided a simple, but accurate, summary of this complex research.

What kind of research was this?

Down's syndrome is a genetic condition where a person has an extra copy of chromosome 21. People affected by Down's syndrome usually have characteristic physical features, tend to have some degree of learning or developmental difficulty, and can also have various other medical problems, including heart conditions.

The reason why the chromosome abnormality occurs is not clear. The one idenitifed risk factor for the condition is maternal age – the older the mother, the higher the risk that her child will develop Down's syndrome. It is estimated that women aged 45 years old have a one in 30 chance of conceiving a child with the condition.

This current piece of research in mice centred on a type of protein called sorting nexin 27 (SNX27). SNX proteins are said to have a function in the connections between nerve cells in the brain. The researchers say that examination of the brains of humans affected by Down's syndrome, and a similar mouse model of the disease, revealed various abnormalities inside the brain. These abnormalities were associated with the connections between nerve cells, including:

  • dendrites – the branches at the ends of the nerve cells
  • synapses – the gaps that electrical signals are passed across to the next nerve cell

This research aimed to look at "a new role for SNX27 in the dysregulation of synaptic function in Down's syndrome" using mice genetically engineered to lack the SNX27 protein.

What did the research involve?

Initially the researchers looked at the brains of normal newborn mice to see how the SNX27 protein is produced inside the brain. They compared normal mice with those genetically engineered to lack protein SNX27, and found mice completely lacking the protein survived well after birth until 14 days. After this point their growth rate slowed, and they died by four weeks. Examination of their brains revealed they had degenerating nerve cells in the brain.

The researchers said that in the immediate period following birth, there is a period of increased brain development (specifically, dendritic branching and synapse formation) that is greatly compromised when the SNX27 protein is lacking.

Because mice genetically engineered to lack the SNX27 protein (labelled Snx27-/-) had such a limited lifespan, the researchers studied mice carrying just one copy of the gene that helps to make the protein (labelled Snx27+/-) so they could examine the effect of a lack of the protein on learning and memory. These mice had a similar life expectancy to the normal mice (labelled Snx27+/+).

The researchers set the mice behavioural tests, such as maze tests, to assess their learning and memory. They then examined the brains of Snx27+/- mice to look at the function of their nerve cells, focusing on the synaptic connections. Finally, the researchers examined brain samples from people with and without Down's syndrome to see if the observations from the mouse experiments were also seen in humans.

What were the basic results?

In the maze test, the researchers found that a week after training, Snx27+/- mice made more errors and had less spatial awareness than normal mice, and also spent less time exploring new objects. However, they were no different in terms of movement ability or vision.

When looking at brain samples from the Snx27+/- mice, they found that these mice had decreased chemical signalling across the synapses compared with normal mice. On further examination, the defect seemed to be on the 'postsynaptic' side.

This means there is a defect with the electrical signal being received by the next nerve cell, rather than a defect with the initial transmission of the electrical signal across the synapse.

They found that loss of the SNX27 protein leads to the breakdown of certain glutamate receptors in the postsynaptic nerve membranes.

When examining human brain samples, the researchers discovered that the amount of SNX27 protein and certain postsynaptic glutamate receptors were markedly decreased in the brains of people with Down's syndrome.

How did the researchers interpret the results?

The researchers conclude that a loss of SNX27 protein contributes to synaptic dysfunction by modulating the glutamate receptors. They say that their "identification of the role of SNX27 in synaptic function establishes a new molecular mechanism of Down's syndrome [disease development]".


This scientific research offers a new insight into how chemical signalling between nerve cells may function in some people with Down's syndrome. Dysfunction of the signalling between nerve cells has previously been suggested to play a role in various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

The researchers say they plan further laboratory research exploring how a lack of SNX27 protein affects postsynaptic receptors.

However, this research does not provide the whole answer to the biological processes behind all of the developmental and physical characteristics of Down's syndrome.

Although the brain samples from people with Down's syndrome were also found to lack SNX27 protein and have reduced glutamate receptors, there may be other biochemical differences that this study has not explored.

Down's syndrome is complex, so it is unlikely that one protein or one chemical signalling pathway will be responsible for all the characteristics – many different biological process are likely to contribute.

The main limitation of this research is that it was mainly in mice. However, some of the experiments used samples of human brain. Further studies in humans are needed to further explore the biological underpinnings of Down's syndrome.

Despite being of scientific interest, this research has no immediate implications for the prevention of Down's syndrome, or for the treatment of any aspects of the condition. However, it does tell us more about the complex causes of this condition.

Research like this, which explores the underlying biology of Down's syndrome, could eventually lead to novel treatments for the condition. However, this is an aspiration rather than a certainty.

Analysis by Bazian
Edited by NHS Website

Links to the headlines

Down's syndrome 'linked to brain protein loss'

BBC News, 24 March 2013

Links to the science

Wang X, Zhao Y, Zhang X, et al.

Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome

Nature Medicine. Published online March 24 2013