Cell stress may play key role in triggering hATTR-PN

A type of cell damage called oxidative stress may be key to the development of disease symptoms in people who carry the most common TTR gene mutation that causes hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), according to a study.

Researchers found that people with symptomatic disease tended to have elevated levels of biomarkers that indicate oxidative stress and inflammation. They also found that oxidative stress may help push the transthyretin (TTR) protein into the abnormal shape that contributes to the disease.

“Our results support a model in which the genetic TTR variant is not the only factor that determines whether and when the disease develops,” Anders Olofsson, PhD, the study’s senior author and a professor at Umeå University in Sweden, said in a university news story. “The body’s ability to maintain a functional [balance of oxidative stress] may also be important.”

The study, “Disrupted glutathione homeostasis in the pathogenesis of TTR-V30M amyloidosis,” was published in Biomarker Research.

“Together, these metabolic alterations suggest a biochemical framework in which inflammation, oxidative stress, and [transthyretin] misfolding may be interconnected,” the researchers wrote. Treatments targeting inflammation and oxidative stress, they wrote, could therefore be “explored as possible complements to existing TTR-targeted therapies.”

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Gene mutation causes protein clumps

Hereditary TTR amyloidosis (hATTR) is a group of progressive conditions caused by mutations in the TTR gene, which result in the production of a misfolded TTR protein. This abnormal protein is prone to form toxic clumps, called amyloid deposits, that accumulate in the body’s tissues and organs, causing damage.

hATTR-PN is a form of the disease characterized mainly by damage to nerves outside the brain and spinal cord. TTR mutations can also cause hereditary transthyretin amyloid cardiomyopathy (hATTR-CM), in which toxic TTR clumps primarily damage the heart.

The Val30Met (V30M) mutation is one of the most common disease-causing TTR mutations, and the most common cause of hATTR-PN. In Sweden, V30M is particularly common in the small northern town of Skellefteå. Because of that, the resulting condition has its own regional nickname, Skellefteå disease.

Although V30M can cause hATTR-PN, not everyone with the mutation will develop symptoms. It’s still unclear why this variability exists, but the new study points to differences in oxidative stress as a possible explanation.

Oxidative stress is a type of cellular damage resulting from an imbalance between the production of potentially harmful molecules, called reactive oxygen species (ROS), and the cells’ ability to clear them with antioxidants.

ROSs are constantly produced as a byproduct of normal cellular activities — kind of like biological exhaust — so the body has systems in place to handle them using antioxidants. One of the body’s most powerful antioxidant defense systems is a molecule called glutathione. When it is broken down, it leads to high levels of another molecule, PGA.

The research team analyzed blood levels of oxidative stress markers in 47 people carrying the V30M mutation and showing symptoms, 30 V30M mutation carriers not showing symptoms (asymptomatic carriers), and 26 healthy people without the mutation (healthy controls).

The researchers found that symptomatic patients had significantly higher blood PGA levels than asymptomatic carriers (by 25%) and healthy controls (by 32%). No significant level differences were found between the two latter groups.

“The majority of symptomatic V30M patients had higher PGA levels than both healthy controls and asymptomatic V30M carriers, consistent with a disease-associated increase in PGA,” the researchers wrote.

This suggests that symptoms are accompanied by a breakdown of one of the body’s most important defenses against oxidative stress.

Data also indicated that symptomatic patients showed significantly elevated activity of the IDO1 enzyme, a marker of inflammation. PGA and IDO1 could, therefore, become “a valuable complement to the clinical monitoring of individuals with hereditary ATTR amyloidosis,” said Anushree Bachhar, PhD, the study’s first author and a postdoctoral researcher at Umeå University.

Combining these two markers allowed the researchers to discriminate between symptomatic patients and healthy controls with an accuracy of 84%.

Taking all these data collectively, the researchers proposed that oxidative stress may play a direct role in driving symptom development in people who carry the V30M mutation. If that’s true, then treatments aimed at reducing oxidative stress may be beneficial.

The scientists called for further studies into oxidative stress markers as potential biomarkers of disease severity and treatment targets.