DEC 04, 2019 9:22 AM PST

Scientists Reverse Cognitive Defects in Down Syndrome Mouse Model

WRITTEN BY: Carmen Leitch

Down syndrome (DS), caused by a chromosome abnormality in which a person carried three copies of chromosome 21, is the primary genetic cause of cognitive disability in the United States. Now researchers have found a drug that can correct the memory and learning impairments that are linked to the disorder. The scientists determined that disruptions in protein production in a part of the brain called the hippocampus are related to the mental deficits caused by the condition, and in a mouse model of DS, those problems can be reversed. The findings have been reported in Science.

A child with Down syndrome / Image credit: Public domain pictures

The cognitive problems linked to DS were thought to be irreversible, noted the researchers. But in the mouse model, called Ts65Dn, drugs targeted a stress response pathway of cells and were able to restore protein levels in the hippocampus to normal. The mice no longer displayed mental deficits. Similar drugs may work on humans.

DS is generally thought of as a genetic disease, but this work focused instead on the production and quality of proteins in the cell, or proteostasis. Co-senior study author Peter Walter, Ph.D. wanted to know more about how proteostasis and DS were connected.

“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 Walter, a professor of Biochemistry and Biophysics at UCSF.

In the mouse model, the scientists applied a technique called polysome profiling, which takes a snapshot of how the protein factories of the cell are functioning. They learned that protein levels were reduced by up to 39 percent in the DS mouse hippocampus, an area linked to memory and learning.

The cells in the hippocampus were triggering a pathway called the integrated stress response (ISR), which is alerted when something is wrong, like the presence of an extra chromosome. A protective response is then triggered, and protein production is ramped down.

“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,” Walter explained.

The researchers assessed brain tissue from DS patients as well as an individual in which only some cells carried an extra copy of chromosome 21 while others were normal. They confirmed that the ISR pathway was active in the cells with the extra chromosome. ISR, therefore, seems to closely related to DS symptoms.

The scientists tried a few different approaches to turn ISR activity down that related to an enzyme called PKR, which has a role in activating ISR in the hippocampus. They deleted the PKR gene, they suppressed PKR activity with a drug, and they activated protein manufacture with a well-known drug that also interferes with ISR. Every strategy improved cognition in the mouse model. The mice exhibited positive behavioral and physiological changes. Their brains were showing signs of improved memory formation at the neurological level.

Walter acknowledged that there is a lot more work to be done. However, this is an important step towards improving the lives of people living with DS.

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

Walter discusses how cells respond to stress in the lecture above.


Sources: University of California San Francisco (UCSF), Science

About the Author
  • Experienced research scientist and technical expert with authorships on 28 peer-reviewed publications, traveler to over 60 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
JAN 11, 2020
Genetics & Genomics
JAN 11, 2020
Single Cells Carry 'Forests' of Chromatin
Researchers are learning more about how every human cell organizes and packages about two meters of DNA....
JAN 27, 2020
Cell & Molecular Biology
JAN 27, 2020
The 3D Ultrastructure of a Cell is Revealed
Seeing what's going on inside of cells presents many challenges that advances in microscopy have tried to address....
FEB 20, 2020
Cell & Molecular Biology
FEB 20, 2020
Fresh Insights Into the Inner Membrane of the Mitochondria
Structures called mitochondria are crucial for life; these small powerhouses generate energy for cells. Scientists have now learned more about these ancient organelles....
FEB 25, 2020
Genetics & Genomics
FEB 25, 2020
Improving Gene Therapy With Plant-Based Relatives of Cholesterol
Cholesterol analogs give nanoparticles a shape that helps them get where they need to go....
MAR 07, 2020
Drug Discovery & Development
MAR 07, 2020
Do Surgical Masks Really Prevent the Spread of COVID-19?
As COVID-19 has spread around the world, there has been a global run on surgical masks. This has led some governments, such as that in India, to ban the ex...
MAR 28, 2020
Cancer
MAR 28, 2020
The Not So Minor Genetic Players in Head and Neck Cancers
Head and neck squamous cell carcinomas (HNSCC) are among the most prevalent cancers among smokers, linked to alcohol consumption, and the human papillomavi...
Loading Comments...