"Mystery" is very much! New mechanism for Alzheimer's disease: brain cells "tamper with" their genes
November 27, 2018 Source: Biological Exploration
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Brains without (left) and with (right) Alzheimer's disease ROBERT FRIEDLAND/SCIENCE SOURCE
Back in the 1970s, scientists discovered that certain cells can rewrite and edit DNA. For example, some immune cells cut off gene fragments (coding proteins that detect or attack pathogens) and stitch the remaining fragments together to create new proteins. . Our B cells rely on this operation to produce about 1 trillion antibodies, enough to withstand a large number of cells, viruses and other attackers.
Now, neuroscientist Jerold Chun from the Sanford Burnham Prebys Medical Discovery Institute led the team to discover that in addition to immune cells, neurons in the human brain also have this phenomenon, genomic reshuffling, also known as somatic recombination.
“The neurons have the ability to change the 'life blueprint',†explains Jerold Chun. This ability has the potential to benefit neurons because it is possible to generate a series of APP variants that enhance learning, memory or other brain functions. However, there is also a risk that this phenomenon may increase the risk of Alzheimer's disease by producing harmful proteins or otherwise damaging brain cells.
Https://doi.org/10.1038/s41586-018-0718-6
What did the new study find?
To find evidence of "genetic recombination" of nerve cells in the brain, neuroscientist Jerold Chun of the Sanford Burnham Prebys Medical Discovery Institute led a team that analyzed 6 healthy elderly and 7 with Alzheimer's disease (non-inherited) Sexually) patients.
They tested whether the cells contained different genetic versions of the amyloid precursor protein (APP), a major source of lesions in the brains of AD patients.
The researchers believe that the APP gene is a good candidate for research, because previous studies have shown that neurons in Alzheimer's patients may contain additional copies of the gene, which may be caused by somatic cell reorganization.
The results show that neurons seem to have thousands of APP gene variants. Some changes include the conversion of a single nucleotide base while others change the DNA of a large fragment and re-weave the remaining parts together.
The Jerold Chun team also found that neurons in Alzheimer's patients contain six times the number of APP gene variants in healthy human nerve cells! Among them, 11 mutations occurred in rare genetic diseases.
Why is the APP gene recombination?
Why is genetic recombination happening? The Jerold Chun team believes that the key lies in reverse transcriptase. When the AAP gene enters the transcriptional program to produce an RNA copy, the reverse transcriptase then prepares a new DNA copy based on the RNA molecule.
Because reverse transcriptase is a "sloppy copier", Jerold Chun believes that the new version of APP produced by reverse transcriptase may not match the original gene, ie, produce different variations of APP. Considering that drugs that block reverse transcriptase are one of the standard treatments for HIV infection, Jerold Chun suggests that this class of drugs may also be resistant to Alzheimer's disease.
Treating AD?
Some scientists hope that there is more evidence that reverse transcriptase has such a role. John Coffin, a virologist at Tufts University in Boston, said it is too early to treat Alzheimer's disease with a reverse transcriptase inhibitor, and more research is needed to validate this idea.
The John Coffin team has not detected signs of somatic genetic recombination from cells from other organs or other genes active in the brain. However, John Coffin speculates that this mechanism is likely to be modifying other genes. If the future is indeed verified, it is expected to bring new directions to other brain diseases such as Parkinson.
Geoffrey Faulkner, a molecular biologist at the University of Queensland in Brisbane, Australia, commented that this is a landmark study and probably one of the biggest discoveries in molecular biology for many years.
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