Hereditary ATTR Amyloidosis

Structure of ATTRv-F64S fibrils isolated from skin tissue of a living patient

Amyloid transthyretin-derived (ATTR) amyloidosis is a degenerative, systemic disease characterized by transthyretin fibril deposition in organs like the heart, kidneys, liver, and skin. ATTR amyloidosis causes peripheral polyneuropathy, cardiomyopathy and dysfunction of organs, often leading to fatal outcomes for patients if untreated.

            In the present study, we extracted pathogenic ATTR amyloid fibrils from the skin of a living patient carrying a rare genetic transthyretinmutation (F64S), and characterised the fibrils using immuno-histochemistry, mass spectrometry and cryo-EM. Using Mass Spectrometry, we show that the mutant form of transthyretin (TTR) is more likely to be incorporated into the amyloid fibrils, and we identify novel post-translational modifications of ATTR fibrils. Importantly, our work demonstrates that a minimal amount of skin tissue (less than ten milligrams) enables the determination of a high-resolution structure (2.8 Å), which shows structural conservation across different tissues and ATTR variants. Fibrils derived from living patients offer the possibility to study filament composition and structure across distinct genotypes, phenotypes and disease stages (fibrils from post-mortem tissue likely reflects the end stages of a disease). Moreover, skin biopsy can be performed longitudinally, enabling within patient follow-up studies that reveal how amyloid fibrils may evolve over time and in response to disease-modifying interventions.

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Structure of ATTRv-F64S fibrils isolated from skin tissue of a living patient.
Yu J*, Zhang X*, Pinton S, Vacchi E, Cavalli A, Pecoraro M, Melli G and Boland A. Nature Communications, 2025.

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We thank all patients for their support of our research and hope that this approach will also be successfully applied to fibrils known to cause neurodegenerative diseases.