Newswise — Over 5,000 individuals receive a yearly diagnosis of ALS (amyotrophic lateral sclerosis), an incurable degenerative ailment that affects neurons in the brain and spinal cord. This relentless disease progressively deprives people of their capacity to communicate, mobilize, consume, and respire, ultimately leading to fatality.
To date, only a handful of drugs exist to moderately slow its progression. There is no cure.
Yet CU Boulder scientists have pinpointed an unexpected addition to the disorder—a time-honored protein resembling a virus, renowned for its contradictory function of facilitating placental growth.
"According to senior author Alexandra Whiteley, an assistant professor in the Department of Biochemistry, our findings propose that the presence of the enigmatic protein called PEG10 in elevated quantities within nerve tissue alters cellular activity, thereby playing a role in the development of ALS."
Supported by financial backing from the ALS Association, the National Institutes of Health, and Venture Partners, Dr. Whiteley's laboratory is presently engaged in unraveling the intricate molecular mechanisms at play and exploring methods to impede the aberrant protein.
"While still in the early stages, there is a promising prospect that these findings could pave the way for an entirely novel category of therapeutic interventions that target the fundamental origins of this disease."
Ancient viruses with modern-day impact
A growing body of research indicates that approximately half of the human genome consists of fragments of DNA that originated from viruses, referred to as retroviruses, as well as transposons, which are virus-like parasites. These genetic remnants are remnants of infections that occurred in our primate ancestors around 30-50 million years ago. Some viruses, such as HIV, are widely recognized for their capability to infect new cells and induce diseases.
In contrast, certain viruses, similar to wolves that have evolved and lost their fangs, have undergone domestication over time. These domesticated viruses have lost their capacity to replicate but persist in the human genome, being transmitted from one generation to another. This process has played a significant role in shaping human evolution and influencing human health.
PEG10, also known as Paternally Expressed Gene 10, is a prime example of a "domesticated retrotransposon." Research indicates that PEG10 has played a crucial role in facilitating the evolution of mammals by contributing to the development of placentas—an essential milestone in human evolutionary history.
Resembling a viral Jekyll and Hyde, studies suggest that when PEG10 is excessively present in inappropriate locations, it has the potential to contribute to various diseases. This includes certain types of cancers as well as a rare neurological disorder known as Angelman's syndrome. The dual nature of PEG10 highlights its complex role in both normal biological processes and pathological conditions.
Whiteley's research represents a groundbreaking achievement as it establishes the first connection between the virus-like protein, PEG10, and ALS. The study demonstrates that ALS patients have elevated levels of PEG10 in their spinal cord tissue, suggesting that it potentially disrupts the mechanisms essential for communication between brain and nerve cells. This discovery sheds light on the possible role of PEG10 in the development and progression of ALS.
According to Whiteley, it seems that the accumulation of PEG10 is a distinguishing characteristic of ALS. She has already obtained a patent for PEG10 as a biomarker, providing a means of diagnosing the disease. This patent showcases the potential of PEG10 as a valuable tool in identifying and detecting ALS in individuals.
Too much protein in the wrong places
Whiteley did not set out to study ALS, or ancient viruses.
Instead, she examines the process by which cells eliminate surplus protein, as an excess of the usually beneficial substance has been linked to additional neurodegenerative conditions, such as Alzheimer's and Parkinson's.
Her laboratory is among six worldwide that research a group of genes known as ubiquilins, which function to prevent the accumulation of troublesome proteins within cells.
In 2011, a research study established a connection between a mutation in the ubiquilin-2 gene (UBQLN2) and certain instances of familial ALS, constituting approximately 10% of ALS cases. The remaining 90% of cases are categorized as sporadic, implying that they are not believed to be inherited.
But it has remained unclear how the faulty gene might fuel the deadly disease.
Utilizing laboratory methodologies and animal models, Whiteley and her colleagues from Harvard Medical School initially embarked on identifying the proteins that accumulate when the UBQLN2 malfunctions and fails to impede their buildup. Out of numerous potential proteins, PEG10 emerged as the predominant candidate at the top of the list.
Subsequently, Whiteley and her research team gathered spinal tissue samples from deceased individuals affected by ALS (provided by the medical research foundation Target ALS) and employed protein analysis, specifically proteomics, to identify any potential proteins that exhibited signs of overexpression.
Again, among more than 7,000 possible proteins, PEG10 was in the top five.
In an independent experiment, the team discovered that when the brakes provided by ubiquilin were essentially compromised, the PEG10 protein accumulated excessively, leading to the disruption of axon development. Axons are responsible for transmitting electrical signals from the brain to the body.
The study found that PEG10 was overexpressed in the tissue of individuals affected by both sporadic and familial ALS, indicating that this virus-like protein may play a crucial role in both forms of the disease.
"The identification of PEG10 as a likely contributor to this disease opens up the possibility of a new target for treating ALS," she stated. "Considering that ALS is a devastating condition with no currently effective therapeutics capable of significantly extending lifespan beyond a few months, this discovery could have a monumental impact."
The research could also provide a deeper understanding of other diseases that arise due to protein accumulation, while also offering valuable insights into the influence of ancient viruses on overall health.
In this case, Whiteley said, the so-called “domesticated” virus could a be rearing its fangs again.
"Although the term 'domesticated' is used relatively, these virus-like activities could potentially act as catalysts for neurodegenerative diseases," she explained. "In this scenario, what may be beneficial for the placenta could have detrimental effects on neural tissue."
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