Virus World

Summary: 

Researchers discovered an unexpected link between the progression of ALS and PEG10, a protein traditionally known for its role in placental development. Overabundance of this protein in nerve tissue has been observed to alter cell behavior contributing to ALS. The team is now studying the molecular pathways involved with a view to inhibiting this rogue protein, potentially paving the way for new therapeutics.

Key Facts:

1. The ancient, virus-like protein PEG10, typically associated with placental development, has been linked to the progression of ALS when present in high levels in nerve tissue.
2. The research marks the first time PEG10 has been connected to ALS, with its accumulation seen as a hallmark of the disease.
3. Research findings suggest that inhibiting the rogue PEG10 protein could potentially lead to a new class of therapeutics for ALS.

Source: University of Colorado

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 that is 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. Whiteley’s lab is now working to understand the molecular pathways involved and to find a way of inhibiting the rogue protein. “It is early days still, but the hope is this could potentially lead to an entirely new class of potential therapeutics to get at the root cause of this disease.”

Ancient viruses with modern-day impact

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.

Too much protein in the wrong places

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 mutation in the ubiquilin-2 gene (UBQLN2) to some cases of familial ALS, which makes up about 10% of ALS cases. The other 90% are sporadic, meaning they are not believed to be inherited. But it has remained unclear how the faulty gene might fuel the deadly disease. Using laboratory techniques and animal models, Whiteley and colleagues at Harvard Medical School first set out to determine which proteins pile up when the UBQLN2 misfires and fails to put the brakes on. Among thousands of possible proteins, PEG10 topped the list. Then Whiteley and her colleagues collected the spinal tissue of deceased ALS patients (provided by the medical research foundation Target ALS) and used protein analysis, or proteomics, to see which if any seemed overexpressed.

Again, among more than 7,000 possible proteins, PEG10 was in the top five. In a separate experiment, the team found that with the ubiquilin brakes essentially broken, the PEG10 protein piles up and disrupts the development of axons—the cords which carry electrical signals from the brain to the body. PEG10 was overexpressed in the tissue of individuals with both sporadic and familial ALS, the study found, meaning the virus-like protein may be playing a key role in both. “The fact that PEG10 is likely contributing to this disease means we may have a new target for treating ALS,” she said. “For a terrible disease in which there are no effective therapeutics that lengthen lifespan more than a couple of months, that could be huge.” The research could also lead to a better understanding of other diseases that result from protein accumulation, as well as keener insight into how ancient viruses influence health. In this case, Whiteley said, the so-called “domesticated” virus could a be rearing its fangs again. “Domesticated is a relative term, as these virus-like activities may be a driver of neurodegenerative disease,” she said. “And in this case, what is good for the placenta may be bad for neural tissue.”

Original research published in eLIfe(May 23, 2023):

 https://doi.org/10.7554/eLife.79452

Novel spinal therapy/delivery approach prevented disease onset in neurodegenerative ALS disease model in adult mice and blocked progression in animals already showing disease symptoms. Writing in Nature Medicine, an international team headed by researchers at University of California San Diego School of Medicine describe a new way to effectively deliver a gene-silencing vector to adult amyotrophic lateral sclerosis (ALS) mice, resulting in long-term suppression of the degenerative motor neuron disorder if treatment vector is delivered prior to disease onset, and blockage of disease progression in adult animals if treatment is initiated when symptoms have already appeared.

Writing in Nature Medicine, an international team headed by researchers at University of California San Diego School of Medicine describe a new way to effectively deliver a gene-silencing vector to adult amyotrophic lateral sclerosis (ALS) mice, resulting in long-term suppression of the degenerative motor neuron disorder if treatment vector is delivered prior to disease onset, and blockage of disease progression in adult animals if treatment is initiated when symptoms have already appeared. The findings are published in the December 23, 2019 online issue of the journal Nature Medicine. Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine and a member of the Sanford Consortium for Regenerative Medicine, is senior author of the study. 

ALS is a neurodegenerative disease that affects nerve cells in the brain and spinal cord. Motor neurons responsible for communicating movement are specifically harmed, with subsequent, progressive loss of muscle control affecting the ability to speak, eat, move and breathe. More than 5,000 Americans are diagnosed with ALS each year, with an estimated 30,000 persons currently living with the disease. While there are symptomatic treatments for ALS, there is currently no cure. The majority of patients succumb to the disease two to five years after diagnosis. There are two types of ALS, sporadic and familial. Sporadic is the most common form, accounting for 90 to 95 percent of all cases. It may affect anyone. Familial ALS accounts for 5 to 10 percent of all cases in the United States, and is inherited. Previous studies show that at least 200 mutations of a gene called SOD1 are linked to ALS. The SOD1 gene normally serves to provide instructions for making an enzyme called superoxide dismutase, which is widely used to break down superoxide radicals — toxic oxygen molecules produced as a byproduct of normal cell processes. Previous research has suggested that SOD1 gene mutations may result in ineffective removal of superoxide radicals or create other toxicities that cause motor neuron cell death, resulting in ALS.

The new approach involves injecting shRNA — an artificial RNA molecule capable of silencing or turning off a targeted gene — that is delivered to cells via a harmless adeno-associated virus. In the new research, single injections of the shRNA-carrying virus were placed at two sites in the spinal cord of adult mice expressing an ALS-causing mutation of the SOD1 gene, either just before disease onset or when the animals had begun showing symptoms....

Published in Nature Medicine (23 Dec. 2019):

https://doi.org/10.1038/s41591-019-0674-1