Summary: Researchers have identified an unexpected connection between amyotrophic lateral sclerosis (ALS) progression and PEG10, an ancient, virus-like protein best known for its role in placental development. Excess PEG10 in nerve tissue appears to alter cellular behavior in ways that contribute to ALS. Scientists are now mapping the molecular pathways behind this effect and exploring ways to inhibit PEG10, a strategy that could open the door to new ALS therapies.
Key Facts:
- The ancient, virus-like protein PEG10, normally linked to placental function, is associated with ALS progression when it accumulates at high levels in nervous tissue.
- This study is the first to connect PEG10 accumulation with ALS, identifying it as a potential hallmark of the disease.
- Inhibiting PEG10 or restoring its normal regulation could become a novel therapeutic approach for ALS.
Source: University of Colorado
More than 5,000 people are diagnosed annually with ALS (amyotrophic lateral sclerosis), a fatal neurodegenerative disease that progressively destroys motor neurons in the brain and spinal cord, ultimately impairing speech, movement, swallowing and breathing.
Current treatments provide modest slowing of disease progression for some patients, but there is no cure. That urgent unmet need motivated researchers at CU Boulder to investigate new molecular drivers of ALS.
The team’s results, published in the journal eLife, reveal a surprising culprit: PEG10, a domesticated retrotransposon-derived protein best known for supporting placental development, is abnormally elevated in ALS spinal cord tissue.
“When PEG10 is present at high levels in nerve tissue, it changes cell behavior in ways that contribute to ALS,” said senior author Alexandra Whiteley, assistant professor in the Department of Biochemistry. Her lab is now working to understand the pathways by which PEG10 interferes with neuronal function and to identify ways to inhibit the protein.
The researchers emphasize that these findings are an early but promising step toward therapies that target the root cause of ALS rather than just treating symptoms. If PEG10 activity can be safely restrained in nervous tissue, it may represent an entirely new class of therapeutics.
Ancient viruses with modern-day impact
About half of the human genome is made up of sequences left behind by ancient viruses and virus-like elements called transposons. Over tens of millions of years these elements have been co-opted by the host genome; some became essential to human biology. PEG10 (Paternally Expressed Gene 10) is one such domesticated retrotransposon that likely helped mammals evolve placentas.
Although domesticated elements can serve useful functions, they sometimes behave detrimentally when misregulated. Prior studies have implicated PEG10 in certain cancers and in Angelman syndrome. This CU Boulder study is the first to show PEG10 accumulation in ALS spinal cord tissue and to link its activity to disruptions in neural function.
Whiteley and colleagues found PEG10 levels elevated in the spinal cords of people with both familial and sporadic ALS, suggesting the protein’s dysregulation may be relevant across forms of the disease. The team also secured a patent for PEG10 as a potential biomarker to aid in ALS diagnosis and monitoring.
Too much protein in the wrong places
Whiteley’s laboratory focuses on how cells remove excess or damaged proteins. Proteostasis—the balance of protein production, folding and clearance—is critical to nervous system health, and its breakdown is a shared feature of many neurodegenerative disorders such as Alzheimer’s, Parkinson’s and ALS.
Her group studies ubiquilins, a family of proteins that help shuttle damaged or excess proteins to degradation pathways. Mutations in UBQLN2, the gene encoding ubiquilin-2, have been linked to some familial ALS cases, but the molecular chain of events from UBQLN2 dysfunction to neuron loss was not well understood.
Using cell models and animal studies in collaboration with colleagues at Harvard Medical School, the researchers examined which proteins accumulate when UBQLN2 function is impaired. Among thousands of candidates, PEG10 rose to the top. Proteomic analysis of postmortem spinal cord tissue from ALS patients confirmed PEG10 was among the most overexpressed proteins compared with healthy controls.
Further experiments showed that when ubiquilin-mediated clearance fails, PEG10 accumulates and disrupts axon development—the growth and maintenance of the long projections that carry electrical signals from the brain to muscles. PEG10’s aberrant activity includes a self-cleavage process that produces a fragment capable of entering the nucleus and altering gene expression programs tied to axon remodeling.
Because PEG10 overexpression appears in both sporadic and familial ALS samples, the protein may play a central role in disease progression for a broad range of patients. That raises the possibility of developing therapies that directly target PEG10 regulation or its downstream effects.
“If we can restore the normal control of PEG10 or block its harmful activity in neurons, that could lead to a meaningful advance for ALS treatment,” Whiteley said. The work also offers insights into how ancient viral elements continue to influence human health today.
About this ALS research news
Author: Lisa Marshall
Source: University of Colorado
Contact: Lisa Marshall – University of Colorado
Image: The image is credited to Neuroscience News
Original Research: Open access. “UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS” by Holly H Black et al. eLife
Abstract
UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron dysfunction and loss. Mutations in the proteasome shuttle factor Ubiquilin 2 (UBQLN2) cause some familial ALS cases, but how UBQLN2 dysfunction drives disease has been unclear.
This study shows that UBQLN2 regulates the domesticated gag-pol retrotransposon PEG10 in human cells and tissues. In cultured cells, the PEG10 gag-pol protein self-cleaves in a retrotransposon-like manner to release a nucleocapsid fragment that localizes to the nucleus and alters the expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol levels are elevated relative to healthy controls.
These results implicate PEG10’s retrotransposon-like activity as a contributing mechanism in ALS through gene expression changes, and identify UBQLN2’s restraint of PEG10 as a key function for maintaining neuronal health.