Down syndrome (DS) is a chromosomal condition that results from having an additional copy of human chromosome 21. It is the leading cause of intellectual disability, for which no effective treatment exists. Since DS is a genetic condition, most studies have been focusing on how the altered genes in DS are causing cognitive dysfunction. However, researchers at UC San Francisco and Baylor College of Medicine have thought outside the box. Instead of focusing on the genes, they decided to look at an important cellular function in the brain, proteostasis, and how it can be affected in DS.
Proteostasis, or protein homeostasis, is the regulation of protein synthesis in the brain and is essential for brain functions like the formation of long-term memory. It is controlled by the integrated stress response (ISR) in the cell. When activated by either external stress (e.g. hypoxia, infection) or internal stress (e.g. build up of bad proteins), ISR works to either repair the stressed cells (often by altering protein production) or induce cell death. Interestingly, researchers found that ISR was highly activated in the brains of both DS mice and human individuals, instigated by an enzyme called PKR. PKR ultimately works to inhibit protein synthesis in cells and is also greatly increased in the hippocampus of DS mice. When scientists inhibited PKR, thereby suppressing ISR and allowing normal proteostasis, the DS mice showed restored cognitive ability and improved long-term memory.
The cognitive dysfunction of DS is previously thought to be irreversible. However, the researchers were able to show, for the first time, that abnormally high activation of the ISR contributes to the cognitive disability associated with DS, and, more excitingly, inhibiting ISR is enough to reverse the cognitive defects in DS mice. This opens up a new promising therapeutic avenue for the treatment of DS, and future research can look into modulating ISR to improve cognitive functions for a range of cognitive disabilities.
Managing Correspondent: Wei Li
Press Articles: Restoring protein homeostasis improves memory deficits in Down syndrome model. Science Daily.
Down Syndrome Memory and Intellect Improved Using Drugs in Mouse Model. Genetic Engineering & Biotechnology News.
Original Scientific Article: Activation of the ISR mediates the behavioral neurophysiological abnormalities in Down Syndrome. Science.