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'Landmark study' shows brain cells revamp their DNA, perhaps sparking Alzheimer's disease | Science

Brains without (left) and with (right) Alzheimer's disease Robert Friedland / Science Source           By Mitch Leslie Nov. 21 , 2018,…

Brains without (left) and with (right) Alzheimer’s disease

Robert Friedland / Science Source

In contrast to most cells in our bodies, the neurons in our brain can scramble their genes, scientists have discovered. This genome tampering may expand the brain’s protein repertoire, but it may also promote Alzheimer’s disease, their study suggests.

“It’s potentially one of the largest discoveries in molecular biology in years,” says Geoffrey Faulkner, a molecular biologist at the University of Queensland in Brisbane, Australia, who was not connected to the research. “It is a landmark study,” agrees clinical neurologist Christos Proukakis of University College London.

Scientists first discovered that certain cells could shuffle and edit DNA in the 1970s. Sommige immuuncellen snijden secties van genen die code voor eiwitten die detecteren of bestrijden patogene en splice de resterende stukken samen om nieuwe varieties te creëren. For example, our B cells can potentially spawn about 1 quadrillion types of antibodies, enough to fend off an enormous range of bacteria, viruses, and other attackers.

Scientists have seen hints that such genomic reshuffling-known as somatic recombination- happens in our brain. Neurons there often differ dramatically from one another. They have often more DNA or different genetic sequences than the cells around them.

To look for definitive evidence of somatic recombination in the brain, neurologist Jerold Chun of the Sanford Burnham Prebys Medical Discovery Institute in San Diego, California, and colleagues analyzed neurons from the donated brains of six healthy elderly people and seven patients who had the noninherited form of Alzheimer’s disease, which accounts for most cases. De onderzoekers hebben getest of de cellen verschillende varianten van het gen voor de amyloïde precursorproteïne (APP) hebben, de bron van de plaques in de hersens of mensen met Alzheimer’s ziekte. APP’s genes were a good candidate to examine, the researchers thought, because one of their previous studies suggested neurons from patients with Alzheimer’s disease can harbor additional copies of the gene, an increase that could arise from somatic recombination.

The scientists’ new analysis, reported online today in Nature shows the neurons appear to carry not one or two variants of the APP genes, but thousands. Sommige veranderingen betroffen de omzetting van enkele nucleotide bases, de DNA subunits die de genetische code opmaken. In some cases, the APP gene variants had jettisoned chunks of DNA, and the remaining sections had knitted together. Chun and his colleagues also discovered that neurons from the patients with Alzheimer’s disease contained about six times as many varieties of the APP gene as did the cells from the healthy people. Blandt de forandringer i neuronerne af de mennesker som havde Alzheimer’s sygdom var 11 mutationer som forekommer i de sjældne arvede former for sygdommen. Neurons from the subjects who died without the disease did not have these mutations.

“Chun proposes to have a constant blueprint that stays with us throughout life, neurons have the ability to change that blueprint.” That capability may benefit neurons by enabling them to generate a medley of APP versions that enhance learning, memory, or other brain functions. On the other hand, somatic recombination may promote Alzheimer’s disease in some people by producing harmful versions of the protein or by damaging brain cells in other ways, the scientists conclude.

Where do all these gene variants come from? Chun and his team think gene reshuffling depends on an enzyme called reverse transcriptase that makes DNA copies of RNA molecules. A new variant could occur when a neuron produces an RNA copy of the APP this step is part of the cell’s normal procedure for producing proteins. However, reverse transcriptase may then recopy the RNA molecule to make a DNA duplicate of the APP gene that slips back into the genomic. But because reverse transcriptase is “a sloppy copier,” Chun says, this new version may not match the original gene, and it may code for a different variant of APP . Drugs that block reverse transcriptase are part of the standard treatment cocktail for HIV infection, and they may also work against Alzheimer’s disease, Chun suggests.

Some scientists want more evidence that this enzyme has a role. “Selv om det ser ut som omvendt transcriptase er involvert, er det mye å gjøre for å fastslå at det er,” sier virologist John Coffin of Tufts University i Boston, som ikke var forbundet med studien. And virologist Steven Wolinsky of Northwestern University’s Feinberg School of Medicine in Chicago, Illinois, cautions that treating Alzheimer’s patients with drugs that inhibit reverse transcriptase would be premature. “We just do not have the data yet” to support their use.

Chun and his colleagues did not detect signs of somatic recombination in cells from other organs or in different genes that are active in the brain. However, Faulkner thinks the process could be revising other genes as well. “If you are looking for a completely new mechanism for generating diversity in the brain , it could also be involved in other brain diseases, such as Parkinson’s disease.

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