Unlike 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 biggest discoveries in molecular biology in years,” says Geoffrey Faulkner, a molecular biologist at the University of Queensland in Brisbane, Australia, who wasn’t 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. Some immune cells snip out sections of genes that code for proteins that detect or fight pathogens and splice the remaining pieces together to create new varieties. Our B cells, for example, 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 often have more DNA or different genetic sequences than the cells around them.
To look for definitive evidence of somatic recombination in the brain, neuroscientist 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. The researchers tested whether the cells harbored different versions of the gene for the amyloid precursor protein (APP), the source of the plaques in the brains of people with Alzheimer’s disease. APP’s gene was a good candidate to examine, the researchers thought, because one of their previous studies suggested neurons from patients with Alzheimer’s disease can harbor extra copies of the gene, an increase that could arise from somatic recombination.
The scientists’ new analysis, reported online today in Nature, shows the neurons seem to carry not one or two variants of the APP gene, but thousands. Some changes involved switching single nucleotide bases, the DNA subunits that make up the genetic code. 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. Among the alterations in the neurons of the people who had Alzheimer’s disease were 11 mutations that occur in the rare inherited forms of the illness. Neurons from the subjects who died without the disease didn’t have these mutations.
“Rather than having one constant blueprint that stays with us throughout life, neurons have the ability to change that blueprint,” Chun proposes. 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 arise when a neuron produces an RNA copy of the APP gene—this step is part of the cell’s normal procedure to produce proteins. However, reverse transcriptase may then recopy the RNA molecule to make a DNA duplicate of the APP gene that slips back into the genome. 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 might also work against Alzheimer’s disease, Chun suggests.
Some scientists want more evidence that this enzyme has a role. “Although it looks like reverse transcriptase is involved, there’s a lot of work to do to establish that it is,” says virologist John Coffin of Tufts University in Boston, who wasn’t connected to the study. 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 don’t 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 a different gene that’s active in the brain. However, Faulkner thinks the process could be revising other genes as well. “You could be looking at an entirely new mechanism for generating diversity in the brain.”
Faulkner and Proukakis emphasize that other groups need to replicate the work to confirm this unexpected finding. But if somatic recombination occurs in neurons, Proukakis says, it could also be involved in other brain diseases, such as Parkinson’s disease.