Amyotrophic lateral sclerosis (ALS): Virus-like protein may be key

• Researchers at the University of Colorado Boulder have discovered a link between an ancient protein with virus-like characteristics, called PEG10, and the development of amyotrophic lateral sclerosis (ALS).
• PEG10, primarily known for its role in placental development, has been found to accumulate in excessive amounts in ALS patients’ spinal cord tissue, potentially disrupting communication between brain and nerve cells.
• These new findings may help identify novel pathways to develop new treatments that could target the underlying cause of ALS, potentially paving the way for improved patient outcomes.

Every year in the United States, an average of 5,000 people receive a diagnosis of amyotrophic lateral sclerosis (ALS), a progressive disease that affects the nervous system by damaging nerve cells in the brain and spinal cord.

The condition gradually deprives people of their capacity to speak, move, eat, and breathe.

There are only a few medications available that can moderately delay its advancement and no cure currently exists.

Now, researchers have identified a link between an ancient protein with virus-like characteristics, primarily recognized for its crucial role in facilitating placental development, with the development of the disease.

The study, published in eLife, found elevated levels of PEG10 in the nerve tissue of ALS patients, suggesting it can alter cellular behavior, thereby playing a role in the development of ALS.

Ancient virus-like protein

The study of the human genome has found that a significant portion of the human genome consists of remnants of viral DNA and similar virus-like entities called transposons.

These genetic elements are remnants of viruses and parasites that infected our primate ancestors approximately 30–50 million years ago.

While some viruses, like HIV, are recognized for their ability to infect cells and cause diseases, others have undergone a process of domestication similar to wolves losing their fangs.

These domesticated retrotransposons have lost their capacity to replicate but have persisted through generations, influencing human evolution and health. One such domesticated retrotransposon is PEG10, short for paternally expressed gene 10.

Research suggests that PEG10 played a pivotal role in facilitating the development of placental tissue in mammals, which was a critical milestone in human evolutionary history.

However, when PEG10 becomes excessively abundant in inappropriate locations, it has the potential to contribute to the onset of certain diseases, including certain cancers and a rare neurological disorder called Angelman syndrome, according to studies.

First study to establish PEG10 and ALS link

In this new study, researchers revealed that ALS patients have high levels of PEG10 in their spinal cord tissue, where it likely disrupts the mechanisms responsible for communication between brain and nerve cells.

The researchers note that the accumulation of PEG10 appears to be a characteristic feature of ALS.

Dr. Alexandra Whiteley, an assistant professor at the University of Colorado Boulder and senior author of the study, explained the background to Medical News Today:

“Mutations in many genes can cause ALS, and UBQLN2 is one of them. We found that when UBQLN2 is mutated, the strange virus-like protein called PEG10 accumulates in the cell. PEG10 looks like a virus, but it’s a human gene. Stranger still, we found that PEG10 behaves like a virus, too. It can form a virus-like particle, and it cleaves itself into smaller pieces like some viruses do. We found that one of those pieces moves into the nucleus and changes gene expression in the cell; specifically, genes involved in neuron function and communication.”

“These data represent a new potential pathway of disease where PEG10 may contribute to neuron dysfunction through these virus-like actions,” Dr. Whiteley explained.

“And perhaps most importantly, we found that PEG10 protein levels are high in both UBQLN2-mediated, as well as sporadic ALS tissue samples compared to healthy individuals,” Dr. Whiteley said.

‘A significant finding’

Dr. Mo Janson, a doctor and medical content creator at Welzo, not involved in this research, told MNT that this research “provides valuable insights into the molecular mechanisms underlying ALS, specifically the role of UBQLN2 and its regulation of the retrotransposon PEG10.”

“The identification of PEG10 as a contributor to ALS through its influence on gene expression and axon remodeling is a significant finding,” Dr. Janson said.

“This study adds to our understanding of the complex pathogenesis of ALS and highlights the importance of investigating non-coding elements and retrotransposons in neurodegenerative diseases,” he added.

Dr. Santosh Kesari, a neurologist, neuro-oncologist, and director of neuro-oncology at Providence Saint John’s Health Center, also not involved in the study, agreed, saying that “this paper opens a new mechanism of how hereditary ALS due to mutations in UBQLN2 can lead to accumulation of PEG10, which leads to neuronal dysfunction.”

New avenues for drug discovery

Dr. Whiteley noted that “the implications of our research for patients and the public are suggestive, since much of our research is focused on the effects of PEG10 in cell lines.”

However, “the discovery of this new regulatory pathway between UBQLN2 and PEG10, and the strange activities of PEG10, will open up new avenues for translational research and drug discovery that we are excited to explore,” Dr. Whiteley explained.

Dr. Kesari noted that the research “identifies a new protein that could lead [to] a new treatment approach for ALS. Further studies in this area can identify new avenues to understand how ALS is caused and lead to potentially newer treatment options.”

Dr. Janson agreed, telling MNT that “understanding the molecular pathway involving UBQLN2 and PEG10 could help in developing targeted therapies or interventions to modulate PEG10 activity and its impact on gene expression.”

“Additionally, the identification of PEG10 as a potential biomarker may contribute to earlier diagnosis or monitoring of disease progression in ALS patients,” Dr. Janson said.

“The findings of this study could have significant implications for future treatments and prevention strategies for ALS. Targeting the PEG10 retrotransposon pathway or modulating its activity could be a potential therapeutic avenue. Developing drugs or interventions that specifically inhibit the self-processing or nuclear localization of the PEG10 gag-pol protein may help mitigate its detrimental effects on gene expression and axon remodeling.”

– Dr. Mo Janson

However, Dr. Janson noted that “further research is needed to fully understand the intricacies of these molecular mechanisms and their potential as therapeutic targets.”

“Nonetheless, this study provides a foundation for future investigations and opens up new avenues for developing treatments and prevention strategies for ALS,” Dr. Janson said.

Dr. Whiteley concluded that this “research is very much in the early stages, but [it] highlights the possibility of opportunity for therapies focused on inhibiting the activities of this virus-like protein as a new avenue for development.”

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