The New Player in ALS—An Ancient, Virus-Like Protein

ALS (amyotrophic lateral sclerosis) is a deadly neurodegenerative disease that attacks nerve cells in the brain and spinal cord, progressively robbing individuals of their capability to speak, move, eat, and breathe.

The New Player in ALS—An Ancient, Virus-Like Protein
Alexandra Whiteley. Image Credit: University of Colorado Boulder

Currently, there are just a few drugs available to moderately limit its advancement - there is no treatment.

However, CU Boulder researchers have discovered an unexpected new player in the disease: an ancient, virus-like protein best known for its vital function in placental development.

The findings were 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.

Alexandra Whiteley, Study Senior Author and Assistant Professor, Department of Biochemistry, University of Colorado Boulder

Her lab is now attempting to understand the molecular pathways involved and to develop a mechanism to suppress the rogue protein, thanks to funding from the ALS Association, the National Institutes of Health, and Venture Partners.

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.

Alexandra Whiteley, Study Senior Author and Assistant Professor, Department of Biochemistry, University of Colorado Boulder

Ancient Viruses With Modern-Day Impact

According to a recent study, almost half of the human genome is made up of fragments of DNA left behind by viruses (called retroviruses) and related virus-like parasites (referred to as transposons) that infected the primate ancestors 30–50 million years ago. Some are well known for their ability to invade new cells and cause sickness, such as HIV.

Others, such as wolves that have lost their fangs, have become domesticated with time, losing their ability to replicate while passing down from generation to generation, impacting human evolution and health.

One such “domesticated retrotransposon” is PEG10, or Paternally Expressed Gene 10. According to research, it most likely aided mammals in developing placentas, an important stage in human evolution.

However, when it is extremely abundant in the wrong areas, it may drive disease, including certain malignancies and a rare neurological disorder called Angelman's syndrome, according to research.

Whiteley’s study is the first to correlate the virus-like protein to ALS, demonstrating that PEG10 is abundant in the spinal cord tissue of ALS patients, where it most likely interferes with the machinery that allows brain and nerve cells to communicate.

It appears that PEG10 accumulation is a hallmark of ALS,” said Whiteley, who has already obtained a patent for PEG10 as a biomarker, or way of diagnosing the disease.

Too Much Protein in the Wrong Places

Whiteley has no intention of researching ALS or ancient viruses.

Instead, she investigates how cells remove extra protein, as extra protein has been linked to other neurodegenerative diseases such as Alzheimer's and Parkinson's.

Her facility is one of a half-dozen in the globe to research a class of genes called ubiquilins, which helps in keeping problem proteins from accumulating in cells.

A study published in 2011 connected a mutation in the ubiquilin-2 gene (UBQLN2) to some cases of familial ALS, which accounts for around 10% of all ALS cases. The remaining 90% are sporadic, which means they are not thought to be inherited.

However, it remains unclear how the defective gene may be driving the deadly disease.

Whiteley and co-workers at Harvard Medical School used laboratory techniques and animal models to first discover which proteins accumulate when the UBQLN2 misfires and fails to put the brakes on. PEG10 ranked above all of the thousands of potential proteins.

The researchers next obtained spinal tissue from deceased ALS patients (supplied by the medical research nonprofit Target ALS) and performed protein analysis, or proteomics, to determine which proteins appeared to be overexpressed.

PEG10 was found once again in the top five of over 7,000 potential proteins.

In a separate experiment, the researchers discovered that when the ubiquilin brakes are pretty much destroyed, the PEG10 protein accumulates and impairs the formation of axons, which are the cords that transmit electrical signals from the brain to the body.

PEG10 was discovered to be overexpressed in the tissue of individuals with both sporadic and familial ALS, implying that the virus-like protein may have a role in both.

The fact that PEG10 is likely contributing to this disease means we may have a new target for treating ALS. For a terrible disease in which there are no effective therapeutics that lengthen lifespan more than a couple of months, that could be huge.”

Alexandra Whiteley, Study Senior Author and Assistant Professor, Department of Biochemistry, University of Colorado Boulder

The study could potentially lead to a better knowledge of other diseases caused by protein buildup, as well as a better grasp of how ancient viruses influence health.

According to Whiteley, the so-called “domesticated” virus may be rearing its fangs once more in this case.

Alexandra Whiteley notes, “Domesticated is a relative term, as these virus-like activities may be a driver of neurodegenerative disease. And in this case, what is good for the placenta may be bad for neural tissue.”

Source:
Journal reference:

Black, H. H. et al. (2023). UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS. ELife. doi.org/10.7554/eLife.79452.

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