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.
Image Credit: Darwin Laganzon from Pixabay
What causes Down Syndrome?
For every baby to be born, the genes of the parents must be equally present. These genes are carried through chromosomes. Each child needs 23 pairs of chromosomes, half of which are inherited from the father and the other half from the mother. In some children, the chromosomes do not separate properly. Because of this, they have an extra chromosome, which can cause mental and physical development problems. This genetic disorder is caused by incorrect cell division in the early stages of cell division of a fertilized egg. For more information on this, you can read the article on the mayoclinic site.
Different forms of this disease
Down syndrome occurs in three different forms, each of which is discussed below.
Trisomy 21: In this type, there is a copy of the extra chromosome in all the cells of the patient’s body. This is the most common type of Down syndrome.
Mosaic syndrome: This complication is also known as mild Down syndrome. Some diseased cells have extra chromosomes. As a result, they have fewer symptoms than people with trisomy 21.
Chromosomal translocation: In this type, the patient has every 23 pairs of chromosomes and only one part of chromosome 21 is copied and there is double the content of that part of the chromosome in the individual cells.
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