Scraps of ancient viruses make up 40% of our genome. They could trigger brain degeneration.
Back in 2008, neurovirologist Renée Douville observed something weird in the brains of people who’d died of the movement disorder ALS: virus proteins.
But these people hadn’t caught any known virus.
Instead, ancient genes originally from viruses, and still lurking within these patients’ chromosomes, had awakened and started churning out viral proteins.
Our genomes are littered with scraps of long-lost viruses, the descendants of viral infections often from millions of years ago. Most of these once-foreign DNA bits are a type called retrotransposons; they make up more than 40 percent of the human genome.
Our genomes are riddled with DNA from ancient viral infections known as jumping genes. The majority of these are retrotransposons, which copy themselves via RNA intermediates; a smaller portion are cut-and-paste DNA transposons.
Many retrotransposons seem to be harmless, most of the time. But Douville and others are pursuing the possibility that some reawakened retrotransposons may do serious damage: They can degrade nerve cells and fire up inflammation and may underlie some instances of Alzheimer’s disease and ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease).
The theory linking retrotransposons to neurodegenerative diseases — conditions in which nerve cells decline or die — is still developing; even its proponents, while optimistic, are cautious. “It’s not yet the consensus view,” says Josh Dubnau, a neurobiologist at the Renaissance School of Medicine at Stony Brook University in New York. And retrotransposons can’t explain all cases of neurodegeneration.
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Yet evidence is building that they may underlie some cases. Now, after more than a decade of studying this possibility in human brain tissue, fruit flies and mice, researchers are putting their ideas to the ultimate test: clinical trials in people with ALS, Alzheimer’s and related conditions. These trials, which borrow antiretroviral medications from the HIV pharmacopeia, have yielded preliminary but promising results.
Meanwhile, scientists are still exploring how a viral reawakening becomes full-blown disease, a process that may be marked by what Dubnau and others call a “retrotransposon storm.”
Genes that jump
A retrotransposon is a kind of “jumping gene.” These pieces of DNA can (or once could) move around in the genome by either copying or removing themselves from one spot and then pasting themselves into a new spot. Retrotransposons are copy-and-pasters.
Many retrotransposons are old companions: Some predate the evolution of Homo sapiens or even the split between plants and animals, Dubnau says. Their predecessors may have alternated between riding along stitched into a host chromosome and existing outside of it, he suggests.
Some retrotransposons, after all that time, retain their ability to hop around human DNA. To do so, they copy themselves with the enzyme reverse transcriptase, which is also used by some viruses like HIV to copy RNA sequences into DNA. Once they’re copied, the remnant viruses can pop into new locations on chromosomes.
If it’s terrifying to think of a genome littered with retroviral genes, some capable of bouncing around the genome, don’t fret, says Douville, now at the University of Manitoba in Winnipeg. Remarkably, some retrotransposons have taken on helpful jobs, assisting the body with tasks like maintaining stem cells and development of the embryo and nervous system.
And many retrotransposons are dormant or broken, and the cell has means to keep them (mostly) quiet. One technique is to stash them in DNA regions that are wound up so tight that the molecular machines needed to copy genes can’t get near them.
In essence, the cell shoves them into a closet and slams the door shut.
But evidence is building that as people age, that closet door can creak open, letting retrotransposons spill out. Exactly what they do then isn’t certain. Some scientists think it’s not so much that they are jumping around and mutating DNA, but that their viralesque RNAs and proteins can screw up normal cellular activities.
“I think what’s actually driving toxicity when transposons are activated is they’re making all these factors that look like a virus to the cell,” says Bess Frost, a neurobiologist at Brown University in Providence, Rhode Island. The cell reacts, quite reasonably, with defensive inflammation, which is commonly associated with neurodegeneration.
Retrotransposons also seem to team up with rogue proteins classically linked to neurodegeneration, damaging or killing nerve cells, and perhaps even setting off the disease in the first place.
Making the ALS connection
Scientists long suspected a link between viruses and ALS, which causes degeneration of the motor neurons that control movement. But the connection, when it was finally found, wasn’t quite what anyone predicted.
In the early 2000s, scientists reported that some people with ALS had the viral enzyme reverse transcriptase in their blood and, more rarely, spinal fluid. Some had as much reverse transcriptase as a person with an HIV infection.
But at the time, says Dubnau, “Nobody could find a virus.”
Finally, Douville and colleagues discovered evidence for one of those leftover viruses, a kind of retrotransposon called HERV-K, in the brains of some people who had died of ALS. From there, scientists began to build a case linking jumping genes to ALS in people, lab animals and cells in dishes. A team reported in 2017 that numerous jumping genes had been activated in the brains of certain people with ALS.
Douville’s colleagues also documented damage inflicted by HERV-K: When they put a gene from the retrotransposon into mice, the animals’ nerve cell projections shriveled and they exhibited ALS-like symptoms.
As the scientists zeroed in on what might be waking up HERV-K, a familiar protein turned up. Called TDP-43, it had already been linked to ALS. But even before that, it was found to be involved in cells’ responses to the retrovirus HIV.
Scientists discovered in the 1990s that TDP-43 works in the cell’s nucleus, where it hinders activation of HIV genes. It also regulates human genes there. But in the neurons of people with ALS or a related condition, frontotemporal dementia (FTD), TDP-43 departs the nucleus and goes on to form abnormal clumps in the cytoplasm. The globs have been associated with a number of neurodegenerative conditions and can spread from cell to cell. And when TDP-43 vacates the nucleus, it also creates a gap in gene regulation, throwing off the activity levels of many genes.
TDP-43 gone bad is sufficient to cause neurodegeneration, but studies indicate its desertion of its nuclear role can also wake up retrotransposons. When TDP-43 leaves the nucleus, tightly coiled DNA next to certain retrotransposons starts to loosen up and unravel, a study of cells from the brains of people who died of ALS or FTD revealed. And researchers saw that in cultured cells, this loss of TDP-43 freed certain retrotransposons from their restraints. The closet door was now ajar, in other words, allowing the retrotransposons to jump out and around.
Meanwhile, Dubnau and collaborators, were looking at data on TDP-43 and the genes it controls in rats, mice and people. They found that TDP-43 can naturally stick to the RNAs of a variety of jumping genes, suggesting a way that normal TPD-43 might continue to corral them, even if they’ve managed to get copied into RNA. That interaction was altered in people with FTD and in rodents with abnormally high or low amounts of TDP-43 — very much as if TDP-43 was unable to control the jumping genes anymore.
The Dubnau group also turned to fruit flies. Both old age and the human TDP-43 gene caused retrotransposons in the fly brain to sneak out of the chromosomal closet, inducing brain cells to kill their neighbors and prompting neurodegeneration, the group reported in a series of papers from 2013 to 2023. Moreover, activation of certain retrotransposons also caused TDP-43 to clump together outside of the nucleus, creating a vicious cycle whereby TDP-43 and the retrotransposons reinforce each other’s abnormal behaviors. Past a certain point, says Dubnau, “It just takes off.”
Based on the sum of all these findings, Dubnau suggests a possible way that ALS could develop: Normally, TDP-43 in the nucleus helps to repress retrotransposons. But if aging or some other disturbance causes TDP-43 to decamp, those once-silenced retrotransposons spring to life, producing virus-like RNAs and proteins. While the retrotransposons might induce disease on their own, by jumping into new DNA locations or spurring inflammation, they also act on TDP-43. They force more TDP-43 to leave the nucleus and clump in the cytoplasm, causing further neurodegeneration that spreads to neighboring cells.
This isn’t the cause of all kinds of ALS, which is a complex disorder with many possible triggers. But in a 2019 study of postmortem brain samples, Dubnau and colleagues found that about one in five people with ALS had high levels of retrotransposon activation and TDP-43 dysfunction.
A link to tau and Alzheimer’s
As that ALS story was developing, other scientists were pursuing a connection between retrotransposons and another toxic protein in neurodegeneration: the tau protein, which twists into unruly tangles in the brain cells of people with Alzheimer’s disease. It affects retrotransposons because it, like TDP-43, plays a role in keeping retrotransposons quiet, says Frost.
That maintenance is a downstream effect of tau’s association with the cell’s interior skeleton. That skeleton is physically linked to the nucleus’s skeletal structure, which in turn anchors the tightly wound-up DNA that silences retrotransposons. When tau goes bad, it changes the structure of the cell’s main skeleton, making it more rigid. Frost and colleagues found that this structural defect propagates all the way to the nuclear skeleton and the chromosomes, just like tightening the strands on one side of a net could change the shape of the other side.
This structural effect can unlock the tightly wound bits of chromosome in fruit flies, which damages their neurons, Frost reported in 2014. By 2018, she’d shown that tau problems unleashed jumping genes in the flies.
“They were legitimately jumping,” she says, going from their original chromosomal locations to other ones in the fly’s brain cells. And the jumping genes contributed to the death of nerve cells.
“They were legitimately jumping.”
Bess Frost
Frost and colleagues also studied mammals — mice — and in 2022 they reported that retrotransposons were also activated in mice with dysfunctional tau.
Meanwhile, Frost and others examined brain cells from people who’d died of tau-related diseases such as Alzheimer’s, which also revealed activated retrotransposons.
This awakening of retrotransposons appears to happen early in the disease, according to the work of another team published in 2022. In blood samples from people on their way to developing Alzheimer’s disease, the copying of retrotransposon genes into RNAs spiked, creating a “retrotransposon storm,” just before their symptoms got bad enough to be labeled Alzheimer’s.
A tactic from HIV treatment
This growing body of evidence suggests that reactivating once-quiet retrotransposons, whether via dysfunctional tau or TDP-43, can create havoc. A potential treatment quickly comes to mind: Since these retrotransposons are a lot like viruses, scientists reason that antiviral drugs could help.
Handily, doctors already have medications that stymie retroviruses: Millions of people take antiretroviral drugs to keep HIV in check or prevent it from gaining a foothold in their cells.
Indeed, multiple studies over several years have investigated drugs from the HIV treatment playbook that block the enzyme reverse transcriptase. And in cells, flies and mice the drugs have dialed down retrotransposon activity and neurodegeneration.
These medications are well understood and generally safe, and are already in trials for neurodegenerative disease. For example, researchers have tested the safety of a 24-week antiretroviral course in 40 people with ALS. Not only did most people safely complete the trial, but the levels of HERV-K in their blood went down, and they seemed to have a delay in progression of their ALS symptoms, the researchers reported in 2019.
Frost recently published results from a small trial in which 12 people with early Alzheimer’s disease took a reverse transcriptase inhibitor for 24 weeks. Her main goal was to determine if the treatment was safe, and it was — but the researchers also observed a drop in signs of inflammation in the participants’ spinal fluid.
Both Dubnau and Frost serve on the scientific advisory board for Transposon Therapeutics, which tested its own reverse transcriptase inhibitor in 42 people with ALS and/or FTD. The company says the drug was tolerable and yielded signs of less neurodegeneration and inflammation, plus a delay in the inevitable worsening of symptoms. The company is planning a larger trial; it also plans to test its drug in people with ALS, Alzheimer’s and a related tau-based disease, progressive supranuclear palsy.
Neither Frost nor Dubnau, who together recently summarized the field for the Annual Review of Neuroscience, believes that antiretroviral drugs alone are the solution to transposon-fueled Alzheimer’s or ALS. As Douville notes, the drugs were designed to act only on specific target enzymes — they won’t do anything to other retrotransposon genes, RNAs or proteins, which could also spur nerve-damaging inflammation.
Meanwhile, scientists are looking beyond ALS and Alzheimer’s as evidence accumulates that retrotransposons may contribute to other neurodegenerative and inflammatory conditions, such as Parkinson’s disease and multiple sclerosis.
“It’s really picking up speed,” Frost says.
This article originally appeared in Knowable Magazine, a nonprofit publication dedicated to making scientific knowledge accessible to all. Sign up for Knowable Magazine’s newsletter.
