A team from the Baylor College of Medicine and the University of California San Francisco has managed to reverse the impairments in mouse models of Down Syndrome. A treatment to reverse intellectual impairments could potentially be translated into humans with the condition someday.
Down syndrome (DS or DNS, also known as trisomy 21) is a cognitive disability caused by a genetic disorder that can affect a person’s memory or ability to learn. It is typically associated with physical growth delays resulting in characteristic facial features. Researchers have long believed the intellectual impairments to be untreatable and irreversible, but now a discovery reveals that those assumptions may not be accurate!
Chromosomes contain a person’s genes. DS is caused by the presence of all, or part, of an extra (third) copy of chromosome 21. Thus the majority of DS research has concentrated on genetics. This new study, however, decided to break away from the norm.
The team focused on the protein-producing cells in the brains of mice with DS instead of their genes. What they discovered is that the animals’ hippocampus region produced 39% less protein than those of mice without DS.
Looking into this further, they determined a likelihood that the presence of an extra chromosome prompted hippocampal cells to trigger an integrated stress response (ISR). Under this response, the result is a decrease in protein production. The research has been published in the journal Science.
Researcher Peter Walter said:
The cell is constantly monitoring its own health. When something goes wrong, the cell responds by making less protein, which is usually a sound response to cellular stress. But you need protein synthesis for higher cognitive functions, so when protein synthesis is reduced, you get a pathology of memory formation.
To test their theory, the team blocked the activity of PKR, the enzyme that prompts the stress response in hippocampal cells. What followed was a reversal of decreased protein production, which then improved the animals’ cognitive function.
By inhibiting the ISR and allowing protein production to carry on, as usual, they were able to reverse cognitive impairment in the mice. However, just because this works in mice doesn’t mean it’ll work in humans.
The researchers then analyzed post-mortem brain tissue samples of humans with DS to see if there were any similarities to the mouse models. They did find evidence that the ISR had been activated. Next, they obtained a tissue sample from a person with DS, one who only had the spare copy of chromosome 21 in some of their cells. They found that those extra cells were the only ones with ISR activated!
Walter said:
We started with a situation that looked hopeless. Nobody thought anything could be done. But we may have struck gold.
Nevertheless, he cautions that there is much more that remains to be studied. The findings are just the beginning steps towards finding therapies that could improve the overall health and lives of people living with down syndrome.
