Extra genes

A new mechanism has been found for alzheimer's mutations

Kirill Stasevich, "Science and Life"

In Alzheimer's disease, as in other neurodegenerative diseases, toxic protein complexes accumulate in the nervous tissue. In the case of Alzheimer's disease, there are two types of such proteins: beta-amyloid and tau protein. They both have their normal functions, but due to mutation, the structure of proteins changes, so that their molecules begin to stick together and poison nerve cells in this form.

Mutations that lead to neurodegenerative diseases are often inherited – and then they talk, for example, about hereditary Alzheimer's disease. But in addition to hereditary Alzheimer's disease, there is also a non-hereditary one, when mutations accumulate in the DNA of neurons during a person's lifetime. It is known that more copies of the APP gene, or beta-amyloid precursor, can be counted in alzheimer's patients. From this precursor, special enzymes then form beta-amyloid itself, and if something is wrong in the APP gene, then beta-amyloid will turn out to be toxic as a result. On the one hand, extra copies of the gene mean that something strange is already happening in the neurons. And now researchers from the Burnham–Sanford–Prebis Medical Institute have managed to find out that these extra copies in addition demonstrate a whole range of mutations.

As we know, the genetic information recorded in DNA is first copied into RNA molecules, and then special molecular machines assemble proteins on RNA molecules. Ming-Hsiang Lee and his colleagues analyzed RNA from neurons of patients with Alzheimer's syndrome, and RNA for analysis was taken from only a few dozen cells. So it was possible to see genetic anomalies that occur with a not very high frequency and that would be lost against the background of more frequent defects if more cells were taken for the experiment. And there really were a lot of very different anomalies in the RNA.

After the cell makes RNA copies from the genes, the RNAs undergo a complex editing called splicing. We will not explain it in detail, suffice it to say that during splicing, some pieces are cut out of the RNA, and the remaining pieces are connected to each other, so that the mature, edited RNA after splicing turns out to be noticeably shorter than the original gene. It turned out that the RNA corresponding to the beta-amyloid precursor gene is found in the neurons of alzheimer's patients in very different variants – the molecules differed in cut pieces, inserts from somewhere, nucleotide substitutions in those places where pieces of recombined RNA were sewn together. And some of these mutations have already been described as concomitant with Alzheimer's disease.

But the strangest thing is that the anomalous shortened, mutant RNA found complete matches in DNA. That is, it looked as if at first there was an ordinary APP gene, from which a long and as yet unedited RNA copy was taken, then this copy was edited with strong errors - and then a copy of DNA was made from the edited copy of RNA and inserted back into the chromosome. As a result, a new copy of the APP gene with embedded mutations was formed in the genome. Such incorrect copies in the cells of patients with Alzheimer's syndrome are 10 times more common than in healthy people. In addition, they can also be found in mice that study Alzheimer's disease.

There is nothing improbable in such a scenario. We have an enzyme reverse transcriptase that synthesizes DNA on an RNA template. In an article in Nature (Somatic APP gene recombination in Alzheimer's disease and normal neurons), the authors of the work write that they managed to provoke the appearance of additional incorrect copies of the APP in cell culture. To do this, it was necessary for reverse transcriptase to work in cells, and for breaks to appear in the cellular DNA, where copies synthesized by reverse transcriptase could be embedded. Finally, it was shown that reverse transcriptase works well in cells taken from the human brain.

Improperly recombined RNAs themselves might not be a big problem – RNA molecules usually don't live very long. But it turns out that mutations resulting from splicing turn out to be recorded in DNA, becoming a constant source of a large set of diverse APP proteins that can give pathogenic beta-amyloid. However, it is worth making a reservation about causes and effects: it is possible that these new copies become the cause of the disease, but it is also possible that the disease begins differently, and new mutant variants of genes are only a consequence (although they may well accelerate the disease).

It is possible that other diseases, like cancer, also arise due to errors in RNA, which are then imprinted in DNA. However, most likely, they are limited to the nervous system, where reverse transcriptase activity is quite high and where breaks in DNA occur more often than in other tissues, where an abnormal copy of the gene can be inserted.

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