PEG10 Might be the Key to Treating Amytrophic Lateral Sclerosis

Thursday - June 22 2023, 15:41 UTC - 1 year ago

CU Boulder researchers have identified a virus-like protein called PEG10 as a promising new target for treating ALS (amyotrophic lateral sclerosis). Studies suggest that when present in high levels, PEG10 can interfere with the normal functioning of the brain and spinal cord. With funding from the ALS Association, the National Institutes of Health, and Venture Partners at CU Boulder, Whiteley's lab is researching how to inhibit PEG10 in order to treat the underlying cause of the fatal disease.

More than 5,000 people are diagnosed annually with ALS (amyotrophic lateral sclerosis), a fatal, neurodegenerative disease that attacks nerve cells in the brain and spinal cord, gradually robbing people of the ability to speak, move, eat, and breathe. To date, only a handful of drugs exist to moderately slow its progression. There is no cure. But CU Boulder researchers have identified a surprising new player in the disease—an ancient, virus-like protein best known, paradoxically, for its essential role in enabling placental development .

The findings were recently published in the journal eLife. "Our work suggests that when this strange protein known as PEG10 is present at high levels in nerve tissue, it changes cell behavior in ways that contribute to ALS," said senior author Alexandra Whiteley, assistant professor in the Department of Biochemistry. With funding from the ALS Association, the National Institutes of Health, and Venture Partners at CU Boulder, her lab is now working to understand the molecular pathways involved and to find a way of inhibiting the rogue protein .

Mounting research suggests about half the human genome is made up of bits of DNA left behind by viruses (known as retroviruses) and similar virus-like parasites, known as transposons, which infected our primate ancestors 30-50 million years ago. Some, like HIV, are well known for their ability to infect new cells and cause disease. Others, like wolves who have lost their fangs, have become domesticated over time, losing their ability to replicate while continuing to pass from generation to generation, shaping human evolution and health .

PEG10, or Paternally Expressed Gene 10, is one such "domesticated retrotransposon." Studies show it likely played a key role in enabling mammals to develop placentas—a critical step in human evolution. But like a viral Jekyll and Hyde, when it’s overly abundant in the wrong places, it may also fuel disease, including certain cancers and another rare neurological disorder called Angelman’s syndrome, studies suggest .

Whiteley’s research is the first to link the virus-like protein to ALS, showing that PEG10 is present in high levels in the spinal cord tissue of ALS patients where it likely interferes with the machinery enabling brain and nerve cells to communicate. "It appears that PEG10 accumulation is a hallmark of ALS," said Whiteley, who has already secured a patent for PEG10 as a biomarker, or way of diagnosing, the disease .

Whiteley did not set out to study ALS, or ancient viruses. Instead, she studies how cells get rid of extra protein, as too much of the typically good thing has been implicated in other neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Her lab is one of a half-dozen in the world to study a class of genes called ubiquilins, which serve to keep problem proteins from accumulating in cells .

In 2011, a study linked a maverick form of the ubiquilin-2 gene to ALS, setting off a flurry of research to understand if that gene, or any related genes, could be a target for treatments.CU Boulder researchers have identified PEG10, an ancient virus-like protein, as a promising new target for treating ALS. Studies suggest that when present in high levels, PEG10 can interfere with the normal functioning of the brain and spinal cord .

With funding from the ALS Association, the National Institutes of Health, and Venture Partners at CU Boulder, Whiteley's lab is researching how to inhibit PEG10 in order to treat the underlying cause of the fatal disease.