A newly discovered biological process protects liver cells from protein buildup in patients with alpha-1-antitrypsin deficiency.
RT’s Three Key Takeaways:
- Polymerized Protein Response: Scientists identified a cellular fail-safe that allows liver cells to tolerate misfolded proteins, explaining why only a subset of patients with alpha-1-antitrypsin deficiency develop liver disease.
- Risk Prediction Improvements: The discovery of this biological pathway could help healthcare providers identify which patients are at the highest risk for severe liver damage and the eventual need for a transplant.
- Broad Therapeutic Potential: The newly identified response may also play a role in other conditions caused by protein aggregation, including amyotrophic lateral sclerosis and certain types of dementia.
Researchers at Washington University School of Medicine in St Louis have identified a previously unknown biological process that may explain why only a subset of patients with alpha-1-antitrypsin deficiency (alpha-1, AATD) develop liver disease, according to a study published in Nature Communications.
AATD is an inherited disorder affecting approximately 100,000 people in the US, typically causing progressive and incurable lung disease. While the condition is primarily known for its respiratory impact, about 10% to 15% of patients also develop liver disease. This occurs when aggregated protein variants, resulting from a genetic error, accumulate in the liver.
The study identifies a cellular fail-safe mechanism dubbed the “polymerized protein response” (PPR). This process appears to protect liver cells from the toxic effects of misfolded, aggregation-prone proteins. The findings may clarify the wide variation in disease severity among patients and inform new methods for predicting which individuals are at the highest risk of requiring a liver transplant.
“What is truly remarkable about proteostasis is that it’s set up to have multiple fail-safes for handling a bad protein,” said David H Perlmutter, MD, executive vice chancellor for medical affairs and dean of WashU Medicine, in a news release. “That’s good for cellular economy because it means the cell doesn’t have to spend all its energy on making every protein perfectly. Our study identifies a completely new way that cells manage potentially harmful proteins.”
The research team found that the PPR allows cells to maintain normal function despite the presence of misfolded proteins that polymerize and aggregate. This mechanism complements the unfolded protein response, which is a well-characterized quality-control process governing how cells handle unfolded proteins.
While both unfolded and aggregated proteins can accumulate in the endoplasmic reticulum—the manufacturing, packaging, and shipping center of the cell—the study shows that cells utilize distinct processes for each. Using human cell lines and mouse models, the researchers demonstrated that aggregated proteins in the liver trigger the PPR through a molecule called Derlin-2, which then activates an NF-kappa-B p50 homodimer to set a protective genetic program in motion.
“We think the polymerized protein response is a cellular adaptation that protects most patients from liver damage due to these aggregated proteins building up in their liver cells,” said Perlmutter, who served as the study’s senior author, in a news release. “It allows the cells to be healthy despite the presence of the proteins. As long as this signal is present, the cells are able to handle the protein load.”
Early identification of this signal could help healthcare providers guide treatment decisions and develop prevention strategies before liver damage becomes apparent. Furthermore, the study found that the PPR could apply to other diseases caused by protein aggregation, including amyotrophic lateral sclerosis (ALS), inherited diabetes insipidus, and certain rare forms of dementia.
