Researchers at CU Boulder have made a groundbreaking discovery linking the virus-like protein PEG10 to the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. PEG10, typically associated with placental development, has been found to alter cell behavior in a detrimental manner when present in high levels within nerve tissue. This finding presents new possibilities for the diagnosis and treatment of ALS.
Promising Target Unveiled for Treating the Underlying Cause of ALS
Every year, over 5,000 individuals receive a devastating diagnosis of ALS, a neurodegenerative disease that gradually attacks nerve cells in the brain and spinal cord, gradually leading to the loss of crucial functions such as speech, movement, eating, and breathing. Currently, there are only a few drugs available that can moderately slow down the progression of the disease, with no cure in sight.
However, researchers at CU Boulder have unveiled an unexpected contributor to ALS—the ancient virus-like protein known as PEG10, primarily recognized for its vital role in facilitating placental development. The results of this study were recently published in the journal eLife.
Dr. Alexandra Whiteley, the senior author and assistant professor in the Department of Biochemistry, stated, “Our work suggests that when this peculiar protein called PEG10 is present in high levels in nerve tissue, it triggers changes in cell behavior that contribute to the development of ALS.”
Dr. Whiteley further emphasized the potential impact of this discovery on ALS treatment, stating, “We may have a new target for treating ALS… This could be groundbreaking for a devastating disease in which current therapeutics only extend lifespan by a couple of months.”
Ancient Viruses: Shaping Our Present Health
Mounting evidence indicates that approximately half of the human genome is comprised of remnants of viral DNA (known as retroviruses) and similar virus-like elements called transposons, which infected our primate ancestors between 30 to 50 million years ago. Some well-known examples, such as HIV, can infect new cells and cause diseases.
Other elements, similar to domesticated wolves losing their fangs, have become integrated into our genetic makeup over time, losing their ability to replicate but still shaping human evolution and health.
PEG10, also referred to as Paternally Expressed Gene 10, belongs to this category of “domesticated retrotransposons.” Studies suggest that PEG10 played a vital role in the evolution of mammals by enabling the development of placentas, a critical step in human evolution. However, this virus-like protein can also contribute to diseases, including certain cancers and the rare neurological disorder called Angelman’s syndrome.
Dr. Whiteley’s research is the first to establish a connection between PEG10 and ALS, demonstrating its presence in high levels within the spinal cord tissue of ALS patients, where it likely interferes with the communication between brain and nerve cells.
According to Dr. Whiteley, “It appears that PEG10 accumulation is a hallmark of ALS.” She has already obtained a patent for PEG10 as a biomarker, allowing for the diagnosis of the disease.
Understanding Protein Accumulation and its Consequences
Dr. Whiteley’s initial focus was not on ALS or ancient viruses. Instead, her research centered around investigating how cells eliminate excess protein, as an excessive amount of proteins has been linked to various neurodegenerative diseases, including Alzheimer’s and Parkinson’s.
Her laboratory is among the few worldwide that study a group of genes called ubiquilins, which help prevent the accumulation of problematic proteins within cells.
In 2011, a study identified a mutation in the ubiquilin-2 gene (UBQLN2) associated with some cases of familial ALS, which constitutes about 10% of all ALS cases. The remaining 90% are sporadic and not considered to be inherited.
However, it has remained unclear how this faulty gene contributes to the development of the fatal disease.
By employing laboratory techniques and animal models, Dr. Whiteley and her colleagues at Harvard Medical School sought to determine which proteins accumulate when the UBQLN2 gene fails to regulate the process effectively. Among thousands of proteins, PEG10 emerged as a prominent candidate.
Furthermore, the team analyzed spinal tissue from deceased ALS patients, generously provided by the medical research foundation Target ALS. By utilizing proteomic analysis, they identified PEG10 as one of the top five overexpressed proteins among more than 7,000 possibilities.
In a separate experiment, the researchers discovered that when the ubiquilin system malfunctions, the PEG10 protein accumulates and disrupts the development of axons—the conduits responsible for transmitting electrical signals from the brain to the rest of the body.
The study found that PEG10 was overexpressed in the tissue of individuals with both sporadic and familial ALS, suggesting a crucial role for this virus-like protein in both forms of the disease.
Dr. Whiteley remarked, “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.”
This research not only holds promise for ALS treatment but also provides insights into other diseases associated with protein accumulation and a deeper understanding of how ancient viruses continue to influence human health.
Dr. Whiteley concluded by stating, “In this case, what is good for the placenta may be bad for neural tissue. These so-called ‘domesticated’ viruses can become drivers of neurodegenerative diseases.”
