Scientists discover a new way that a disease-linked protein comes apart

LA JOLLA, CA—Transthyretin amyloid disease (ATTR) is a progressive, life-threatening condition caused when the protein transthyretin (TTR) breaks apart and aggregates in the heart and other organs. One of the most common treatments, a drug called tafamidis, works by helping TTR stay intact—slowing how it normally unfolds and aggregates. Now, Scripps Research scientists have discovered a second, previously unknown TTR unfolding pathway that may cause protein aggregation in some rare hereditary forms of the disease.

The study, published in the Proceedings of the National Academy of Sciences on September 8, 2026, may offer new avenues of research to treat a condition that affects tens of thousands of people in the United States.

TTR is a protein that helps transport vitamin A and the thyroid hormone thyroxine in the blood, cerebrospinal fluid and the eye. Over time, its four-unit structure splits into two-unit pieces, which then separate into single units that can misfold and clump together—causing one of the most common forms of systemic amyloidosis in humans, particularly in the heart and nervous system.

To uncover the alternative pathway, the researchers tested more than 100 TTR variants, measuring how quickly each unfolded across a range of urea concentrations and acidity levels. They supported their findings using cryogenic-electron microscopy and previously published X-ray crystal structures.

The results reveal that TTR has a second unfolding route in which the four-unit structure falls apart more directly, without the two-unit intermediates. The alternative pathway is accessible to some TTR variants, particularly those that cause amyloidosis in the brain.

“We need to understand whether this alternative pathway can lead to TTR aggregation in the cerebrospinal fluid, which could potentially translate into worse outcomes for patients carrying these rare mutations who take the current medications,” says senior author Jeffery Kelly, the H. Lutcher Brown Endowed Chair at Scripps Research who co-developed tafamidis.

The alternative pathway is also favored under acidic conditions—the environment found inside lysosomes, the cellular organelles where proteins are broken down and recycled at the end of their life cycle.

“This route probably evolved so TTR can be degraded, which is important, but can also have side effects,” says co-author Martin Gruebele, a professor emeritus of chemistry at the University of Illinois Urbana-Champaign.

For people with the most common types of TTR amyloidosis, the alternative pathway appears too slow under normal conditions to compete with the known pathway. But certain disease-associated mutations appear to make the new pathway more accessible, even at normal acidity levels in the blood.

“More research is needed, but this opens up a new direction in the field of drugs targeting specific amyloidosis pathways,” says Gruebele. “At least we have one of several possible smoking guns to look at.”

Besides possible biomedical implications, this paper also furthers our understanding of protein folding and unfolding. Folding through multiple pathways has been proposed by theorists, but demonstrating the existence of such pathways experimentally has been difficult.

“Transthyretin is the first oligomeric protein for which pathway multiplicity has been shown in solution, and without mechanical pulling,” says Marcus Jäger, the first author.

In addition to Jäger, Kelly and Gruebele, authors of the study “Transthyretin can denature by an alternative pathway,” include Jan-Hannes Schäfer, Gabriel Lander and Evan Powers of Scripps Research.

This work was supported by the National Institutes of Health (grant R01 DK046335) and a postdoctoral fellowship from the German Research Foundation (Project No.: 556478029).