The genetic legacy of an ancient virus may help shed further light on the origin of amyotrophic lateral sclerosis (ALS). PEG10 is one of countless formerly viral genes in the human genome that have taken on new tasks in various tissues. The most important is to help with the formation of the placenta. But now researchers led by Alexandra Whiteley from the University of Colorado at Boulder (UC Boulder) have found increased amounts of the PEG10 protein in the nerve tissue of ALS patients.
Normally, a gene called ubiquilin 2 provides the right amount of PEG10. In ALS patients, however, the regulator gene is often mutated and no longer slows down PEG10 production. The ubiquilin-2 mutation was already known, but it was unclear how it leads to the development of ALS, the researchers write in the journal eLife.
They are therefore investigating in cell cultures and animal experiments which proteins accumulate when this mutation is present. PEG10 ended up at the top of the list. When they then examined the spinal cord tissue of deceased ALS patients, PEG10 was also one of the five most common proteins here.
As Whiteley’s group found out in further experiments, the excess PEG10 interferes with the reading of various genes and, as a result, hinders the formation of the long nerve process of the nerve cells, called the axon. However, these normally transmit the electrical control signals from the brain to the muscles.
Prohibited control commands
ALS, also known as Lou Gehrig’s syndrome, is a fatal neurodegenerative disease. It gradually destroys motor nerve cells in the brain and spinal cord so that they can no longer transmit the brain’s control commands to the muscles. The result is muscle paralysis. Patients are deprived of their ability to move, swallow, speak, and breathe.
ALS can also be associated with dementia that develops in the frontal and temporal lobes of the brain, leading to personality and behavioral changes (frontotemporal dementia). The hereditary form of ALS accounts for about ten percent of all cases. In 90 percent of cases, however, the disease occurs “sporadically”, i.e. suddenly. The PEG10 gene is transcribed too strongly in both groups.
According to the German Center for Neurodegenerative Diseases e. V. according to up to 9,000 people with ALS, with around 2,500 new cases every year. One of the best-known ALS patients was the physicist and cosmologist Stephen Hawking.
No cure so far
Some medications can slow the progression of the disease. However, there is no cure. Therefore, Whiteley and colleagues hope that “a better understanding of the biology of PEG10 in the context of ALS and other diseases in which PEG10 is elevated may open new avenues for the development of therapies,” they write in their publication.
“The fact that PEG10 likely contributes to this disease means we may have a new target for treating ALS,” Whiteley told the UC Boulder University Newspaper. “For a terrible disease that has no effective therapeutics that extend life expectancy by more than a few months, this could be very important.”
With financial support from the ALS Association, the US National Institutes of Health and Venture Partners, her group is now trying to elucidate the molecular pathways involved and to find an approach to inhibiting the renegade protein. Whiteley has filed a patent for the use of PEG10 as a biomarker and diagnostic aid for ALS.
Ancient viruses, current effect
The PEG10 gene once encoded part of a virus envelope. It is estimated that such genes from retroviruses make up up to 50 percent of our DNA. Retroviruses have RNA as their genetic material, they write it into DNA after infecting cells so that the cell reads it and builds new virus particles. This is how the HI virus works, for example. But many earlier, often ancient, retroviruses lost their fangs, so to speak, when parts of their genome were incorporated into ours.
These pieces of DNA, called retrotransposons, which can migrate into the genome, are inherited, but no longer produce virus particles. They were, as the biologists say, domesticated. Just as wild animals no longer bite after their domestication, but even support their owners, retrotransposons serve us in various functions. In some cases, like PEG10 with its placenta-forming properties, they even enable an evolutionary leap in development.
In the wrong tissue, however, an excess can also trigger diseases. PEG10 is no stranger to this: too much of it has also been linked to the neurological condition Angelman syndrome, where it disrupts brain development in the embryonic phase. Overproduction can also trigger various types of cancer such as liver carcinoma and chronic lymphocytic leukemia.