TTR protein found to unfold via alternative pathway in acidic conditions

Scripps Research scientists found that transthyretin (TTR), the protein behind ATTR amyloid disease, can unfold through a previously unknown route that bypasses intermediate pairs. The pathway is more accessible in acidic lysosomes and in rare inherited variants, raising questions about how well tafamidis treats them.

• More than 100 TTR variants tested across acidity levels and urea concentrations
• Alternative route is favored in acidic lysosomes and in brain-amyloid mutations
• Tafamidis stabilizes the TTR tetramer, but some variants may need other approaches
• The study was published September 8, 2026, in PNAS