Can Down's disease be cured?
Scientists have discovered a gene that will help cure Down's disease
Experiments on chimeric mice helped American molecular biologists to isolate a gene whose increased activity leads to the development of dementia in carriers of Down syndrome. Their findings and potential methods of "disabling" this DNA site were presented in the journal Cell Stem Cell (Xu et al., OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome)
In recent years, biologists have discovered several genes and "problematic" areas of the brain, the work of which is most disrupted in carriers of Down syndrome. These discoveries leave hope for the creation of gene therapy or drugs that would help correct these disorders and allow children with an extra chromosome to develop normally.
Scientists, as noted by Jiang and his colleagues, have long drawn attention to the fact that the appearance of an extra 21 chromosomes in the DNA of carriers of this disease in a special way changes how inhibitory and excitatory nerve endings were formed in the brain of the embryo.
What exactly happened, neurophysiologists could not say, since experiments on rodent embryos and on brain slices of elderly carriers of Down syndrome ended with the fact that their authors came to the opposite conclusions.
However, these experiments showed that problems with mental development were most likely associated with the OLIG1 and OLIG2 genes. They are responsible for the formation of the so-called GABA neurons, the main "brakes" of our nervous system, and the first section of DNA suppresses their formation, and the second accelerates this process.
How exactly their work is disrupted, scientists did not know. Jiang and his team suggested, based on the results of experiments with miniature copies of the brain, that cognitive problems in carriers of Down syndrome developed due to excessively high activity of OLIG2 and an excess of "inhibitory" receptors.
They tested this theory in an unusual way – they took tissue samples from people who had an extra 21 chromosomes, turned them into stem cells capable of turning into GABA neurons, and injected them into the brains of newborn mice. In the following days and months, biologists observed the development of such "chimeric" rodents, tracking changes in their behavior and in the structure of the brain.
As it turned out, the cortex and other parts of the nervous system of such mice contained significantly more GABA neurons than similar parts of the body of their relatives from the control group, into whose brain scientists injected stem cells with a normal set of chromosomes.
Having obtained similar results, Jiang and his colleagues tested what would happen if the activity of OLIG2 was reduced to normal levels with the help of short RNA molecules that prevented brain cells from reading this part of the genome.
We found out that the OLIG2 gene is one of the most interesting "targets" in order to eliminate abnormalities in the development of the embryo associated with Down syndrome. Its suppression restores the balance between excitatory and inhibitory neurons, which improves cognitive functions after birth," said Peng Jiang from Rutgers University in New Brunswick (in a press release Targeting Key Gene Could Help Lead to Down Syndrome Treatment)
Down syndrome is still the most common cause of dementia on Earth. In the past, scientists believed that it occurs on average in one out of eight hundred inhabitants of the planet, but recent observations by American doctors show that the frequency of its development has at least doubled.
All disorders in the mental development of its carriers arise for the reason that their DNA contains not two, but three copies of the 21st chromosome. As a result, the work of genes responsible for the formation and functioning of the brain is disrupted, which is why their carriers lag behind their peers in mental development from the very first days of life.
In recent years, biologists have discovered several genes and "problematic" areas of the brain, the work of which is most disrupted in carriers of Down syndrome. These discoveries leave hope for the creation of gene therapy or drugs that would help correct these disorders and allow children with an extra chromosome to develop normally.
Scientists, as noted by Jiang and his colleagues, have long drawn attention to the fact that the appearance of an extra 21 chromosomes in the DNA of carriers of this disease in a special way changes how inhibitory and excitatory nerve endings were formed in the brain of the embryo.
What exactly happened, neurophysiologists could not say, since experiments on rodent embryos and on brain slices of elderly carriers of Down syndrome ended with the fact that their authors came to the opposite conclusions.
However, these experiments showed that problems with mental development were most likely associated with the OLIG1 and OLIG2 genes. They are responsible for the formation of the so-called GABA neurons, the main "brakes" of our nervous system, and the first section of DNA suppresses their formation, and the second accelerates this process.
How exactly their work is disrupted, scientists did not know. Jiang and his team suggested, based on the results of experiments with miniature copies of the brain, that cognitive problems in carriers of Down syndrome developed due to excessively high activity of OLIG2 and an excess of "inhibitory" receptors.
They tested this theory in an unusual way – they took tissue samples from people who had an extra 21 chromosomes, turned them into stem cells capable of turning into GABA neurons, and injected them into the brains of newborn mice. In the following days and months, biologists observed the development of such "chimeric" rodents, tracking changes in their behavior and in the structure of the brain.
As it turned out, the cortex and other parts of the nervous system of such mice contained significantly more GABA neurons than similar parts of the body of their relatives from the control group, into whose brain scientists injected stem cells with a normal set of chromosomes.
Having obtained similar results, Jiang and his colleagues tested what would happen if the activity of OLIG2 was reduced to normal levels with the help of short RNA molecules that prevented brain cells from reading this part of the genome.
Such "gene therapy" was a complete success – the number of "extra" cells in the brain of mice significantly decreased, so that the new generation of chimeras did not suffer from serious memory problems characteristic of the first group of rodents.
In particular, they remembered objects unfamiliar to them just as well and found a way out of the maze just as quickly as their relatives with a normal set of chromosomes.
Scientists hope that further experiments with mice and a more detailed study of the work of OLIG2 will help them find a full-fledged cure for Down syndrome, which will not only act on embryos and newborns, but also on adult carriers of this disease.
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