Researchers at Umeå University have identified changes in the body’s major antioxidant systems in patients with hereditary transthyretin (TTR) amyloidosis. From left Anushree Bachhar, Melisnur Sahin, Intissar Anan och Anders Olofsson.
Photo Credit: Umeå university
Scientific Frontline: Extended "At a Glance" Summary: Hereditary ATTR Amyloidosis and Redox Imbalance
The Core Concept: Hereditary ATTR amyloidosis is a progressive, genetic condition characterized by the misfolding of the transthyretin (TTR) protein into tissue-damaging amyloid deposits. Recent research demonstrates that a disrupted antioxidant balance and the resulting oxidative stress act as critical triggers for the clinical onset of the disease.
Key Distinction/Mechanism: While the hereditary TTR-Val30Met mutation provides the underlying vulnerability, the actual development and timing of symptoms are heavily influenced by a failure in the body's redox balance. Specifically, elevated levels of pyroglutamate (PGA) and increased activity of the inflammatory enzyme IDO1 indicate disrupted glutathione metabolism, which precipitates the active disease state.
Major Frameworks/Components:
- Transthyretin (TTR) Misfolding: The structural deformation of the TTR protein, leading to toxic amyloid accumulation in tissues.
- Redox Balance: The essential physiological equilibrium between oxidizing and reducing processes within cells.
- Glutathione (GSH) Pathway: One of the body's primary antioxidant defense mechanisms that protects cellular structures from oxidative stress.
- PGA and IDO1 Biomarkers: Measurable biological indicators reflecting altered glutathione metabolism (PGA) and inflammatory activation (IDO1).
Branch of Science: Molecular Biology, Biochemistry, Genetics, and Clinical Pathology.
Future Application: The identification of these biomarkers has enabled the development of predictive models capable of identifying high-risk, presymptomatic individuals with 80% accuracy in women and nearly 90% in men. This paves the way for advanced clinical monitoring and experimental therapies targeting the body's antioxidant defenses.
Why It Matters: Predicting exactly when an asymptomatic mutation carrier will transition to active disease allows clinicians to introduce preventive measures and targeted interventions before irreversible tissue damage occurs in the heart, nerves, and gastrointestinal tract.
Researchers at Umeå University have identified changes in the body’s major antioxidant systems in patients with hereditary transthyretin (TTR) amyloidosis. The findings support the hypothesis that oxidative stress contributes to disease development and also identify new biomarkers that may help detect individuals at increased risk of developing the disease. The results have been published in the journal Biomarker Research.
ATTR amyloidosis is a serious and progressive disease in which the protein transthyretin (TTR) misfolds and forms amyloid deposits in the body’s tissues. These deposits can damage the nerves, heart, gastrointestinal tract, and other organs. In northern Sweden, the disease is relatively common because of the hereditary TTR-Val30Met mutation, which has given rise to the name “Skellefteå disease.”
Although the genetic cause has been known for many years, it remains unclear why some mutation carriers develop the disease early, others later in life, and some not at all.
In the current study, the researchers investigated whether the body’s redox balance—the balance between oxidizing and reducing processes—may play an important role in disease development. Attention was given to glutathione (GSH), which is one of the body’s most important defenses against oxidative stress.
The results showed that patients with clinically manifest ATTR amyloidosis had markedly elevated levels of pyroglutamate (PGA), a marker that reflects glutathione metabolism. The researchers also found signs of increased activity of the enzyme IDO1, which is associated with inflammation. Taken together, the findings indicate that disrupted antioxidant balance and inflammatory activation are closely linked to disease development.
“Our results support a model in which the genetic TTR variant is not the only factor that determines whether and when the disease develops. The body’s ability to maintain a functional redox balance may also be important,” says Anders Olofsson, associate professor and senior lecturer at the Department of Clinical Microbiology at Umeå University, who led the study.
New Biomarkers May Identify Individuals at Risk
The findings have also enabled the development of a biomarker model based on PGA and the inflammatory marker IDO1. The model can identify individuals at increased risk of developing the disease with an accuracy of approximately 80 percent in women and close to 90 percent in men.
The results raise the possibility of identifying mutation carriers who are approaching the onset of symptoms and introducing appropriate preventive measures before tissue damage becomes permanent.
“These biomarkers could become a valuable complement to the clinical monitoring of individuals with hereditary ATTR amyloidosis,” says the study’s first author, Anushree Bachhar, a postdoctoral researcher at the Department of Clinical Microbiology at Umeå University.
May Pave the Way for New Treatment Strategies
The findings also strengthen the hypothesis that oxidative stress and inflammation contribute to the disease process. This raises the question of whether treatments that affect the body’s antioxidant defenses could slow or delay disease development.
However, the researchers emphasize that the current study does not demonstrate that antioxidant treatment is effective in ATTR amyloidosis. Clinical studies in which the effects of different interventions are monitored over time will be required to investigate this possibility. Work to initiate such studies is ongoing and is considered a high priority.
About the Study: The study included blood samples from healthy controls, asymptomatic carriers of the TTR-Val30Met mutation, and patients with symptomatic ATTR amyloidosis. The researchers analyzed markers of glutathione metabolism and inflammation to investigate their association with disease development.
The study was conducted through a collaboration between researchers and clinicians at Umeå University and was supported by, among others, FAMY-Norr and FAMY-Västerbotten, the Swedish Research Council, the Umeå University Foundation for Medical Research, the Northern Sweden Heart Foundation, and the Kempe Foundations.
Published in journal: Biomarker Research
Title: Disrupted glutathione homeostasis in the pathogenesis of TTR-V30M amyloidosis
Authors: Anushree Bachhar, Gabriella Johannson, Melisnur Sahin, Sanduni Jayaweera, Malin Olsson, Intissar Anan, and Anders Olofsson
Source/Credit: Umeå University | Ingrid Söderbergh
Edited by: Scientific Frontline
Reference Number: mbio071926_01
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