Down Syndrome Intellectual Deficits Reversed in Mouse Model

The news brings hope that the treatment can some day be applied to humans.

Researchers from the University of California San Francisco and Baylor College of Medicine were successful at reversing the learning and memory deficits associated with down syndrome in mice. The news brings hope that some day the process can be applied to humans.

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Cellular stresses

The reversal was done with drugs that target the body’s response to cellular stresses. The researchers discovered that some of down syndrome's intellectual impairments may be traced to altered protein production in the hippocampus.

By administering drugs that target one of the cell’s key stress response pathways, they were able to bring protein levels back to normal. This, in turn, caused the down syndrome-related cognitive deficits to disappear. 

This is a whole new approach to studying down syndrome as most studies focus on the extra copy of chromosome 21 present in those that suffer from the condition.

“The vast majority of the field has been focusing on individual genes on chromosome 21 to figure out which ones are causally related to Down syndrome and its pathologies. Our approach was different. We were trying to uncover a link between proteostasis defects and DS,” said Peter Walter, PhD, professor of Biochemistry and Biophysics at UCSF and co-senior author of the new study.

The researchers found that up to 39% less protein was being produced in the hippocampus of down syndrome mice. The question they then sought to examine was why extra copies of genes could lead to a decline in protein production.

Integrated stress response

They found that the extra chromosome was triggering an integrated stress response (ISR), a biological circuit that is activated when something is off. The ISR was engaging a protective response that limited protein production

“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,” said Walter. 

From there they deduced that by blocking the enzyme responsible for ISR production, the PKR, they could return protein levels to normal and reverse cognitive impairments. Although the study is still just in mice, it offers some very promising results.

“We started with a situation that looked hopeless,” Walter said. “Nobody thought anything could be done. But we may have struck gold.”

 

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