Amyloid fibrils underlie a range of human diseases. We determined the first cryo-EM structure of ATTR filaments from a living patient — from a minimally invasive skin biopsy.
Amyloid transthyretin-derived (ATTR) amyloidosis is a degenerative, systemic disease in which transthyretin fibrils deposit in organs such as the heart, kidneys, liver and skin, causing peripheral polyneuropathy, cardiomyopathy and organ dysfunction — often fatal if untreated.
We extracted pathogenic ATTR fibrils from the skin of a living patient carrying a rare transthyretin mutation (F64S) and characterised them by immunohistochemistry, mass spectrometry and cryo-EM. Mass spectrometry showed the mutant form of transthyretin is preferentially incorporated into fibrils, and revealed novel post-translational modifications.
Crucially, less than ten milligrams of skin tissue was enough to determine a 2.8 Å structure, which proved structurally conserved across tissues and ATTR variants. Because skin biopsies are minimally invasive and repeatable, fibrils from living patients open the door to studying composition and structure across genotypes, phenotypes and disease stages — and to longitudinal, within-patient follow-up of how fibrils evolve over time and respond to treatment. (Fibrils from post-mortem tissue likely reflect only end-stage disease.)
Artistic renderings of the structure, with thanks to Prof. Francisco J. Enguita, University of Lisbon.
We thank all patients for supporting this research, and hope the approach can be extended to fibrils that cause neurodegenerative disease. Work carried out with collaborators in Bellinzona.
Nature Communications · 2025Structure of ATTRv-F64S fibrils isolated from skin tissue of a living patient