A "flagship study" shows that brain cells alter their DNA, possibly causing the onset of Alzheimer's disease | Science

Scientists have discovered that unlike most cells in our body, neurons in our brains can scramble their genes. Their study suggests that this genome modification may broaden the brain's repertoire of proteins, but it may also promote Alzheimer's disease.

"This is potentially one of the greatest discoveries in molecular biology for years," says Geoffrey Faulkner, a molecular biologist at the University of Queensland in Brisbane, Australia, who did not participate in the research. "It's a historical study," confirms clinical neurologist Christos Proukakis of University College London.

Scientists found for the first time that some cells could mix and edit DNA in the 1970s. Some immune cells extract gene fragments that code for pathogen-detecting or anti-pathogenic proteins and then splice fragments. remaining to create new varieties. Our B cells, for example, can potentially generate about 1 quadrillion types of antibodies, enough to counter a considerable number of bacteria, viruses, and other attackers.

Scientists have seen clues that such a genomic rehandling – known as somatic recombination – occurs in our brain. Neurons often differ considerably from one another. They often have more DNA or different genetic sequences than the cells that surround them.

To find definitive evidence of somatic recombination in the brain, neuroscientist Jerold Chun of Sanford San Diego Burnham Prebys Medical Discovery in San Diego, Calif., And colleagues analyzed neurons from the brains of six healthy elderly people and seven patients with the non-inherited form. of Alzheimer's disease, which accounts for most cases. The researchers tested whether cells harbored different versions of the amyloid precursor protein (APP) gene, the source of plaques in the brains of people with Alzheimer's disease. The researchers felt that the APP gene was a good candidate because one of their previous studies had suggested that the neurons of Alzheimer's patients could harbor extra copies of the gene, an increase that could result from somatic recombination.

The new analysis of scientists, published online today at Nature, shows that neurons do not seem to carry one or two variants of the APP gene, but thousands. Some changes have involved the switching of single nucleotide bases, the DNA subunits that make up the genetic code. In some cases, the APP gene variants had dropped DNA fragments and the remaining sections had bound. Chun and his colleagues also found that the neurons of patients with Alzheimer's disease contained about six times more varieties of APP gene like the cells of healthy people. Among the alterations in the neurons of people with Alzheimer's disease were 11 mutations that occur in rare hereditary forms of the disease. The neurons of subjects who died without the disease did not have these mutations.

"Rather than having a consistent pattern that stays with us throughout life, neurons have the ability to change that pattern," Chun suggests. This ability can benefit neurons by allowing them to generate a mix of APP versions that enhance learning, memory, or other brain functions. On the other hand, scientists conclude that somatic recombination can promote Alzheimer's disease in some people by producing harmful versions of the protein or by damaging brain cells in other ways.

Where do all these gene variants come from? Chun and his team believe that gene shuffling is dependent on an enzyme called reverse transcriptase that makes copies of DNA molecules of RNA. A new variant could occur when a neuron produces an RNA copy of the APP gene: this step is part of the normal procedure of the cell to produce proteins. However, the reverse transcriptase can then copy the RNA molecule to produce a duplicate DNA of the APP gene that comes back into the genome. But since reverse transcriptase is "a sloppy copier," says Chun, this new version might not match the original gene and code for a different variant of APP. Drugs that block reverse transcriptase are part of the standard treatment cocktail for HIV infection and could also work against Alzheimer's disease, suggests Chun.

Some scientists want more evidence that this enzyme has a role. "Although it seems that reverse transcriptase is involved, there is a lot of work to be done to prove it," says virologist John Coffin of Tufts University in Boston, who did not participated in the study. And virologist Steven Wolinsky of the Feinberg School of Medicine at Northwestern University in Chicago, Illinois, warned that it would be premature to treat patients with Alzheimer's disease with drugs that inhibit reverse transcriptase. "We do not have the data yet" to justify their use.

Chun and his colleagues have not detected signs of somatic recombination in cells of other organs or in a different gene that is active in the brain. However, Faulkner thinks that the process could also modify other genes. "You could consider an entirely new mechanism for generating diversity in the brain."

Faulkner and Proukakis point out that other groups must duplicate the work to confirm this unexpected discovery. But if somatic recombination occurs in neurons, says Proukakis, he could also be involved in other brain diseases, such as Parkinson's disease.