Saelices Gomez, L. | bioRxiv Science

bioRxiv2024

ATTRv-V30M Type A amyloid fibrils from the heart and nerves exhibit structural homogeneity.

ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid hormones. Transthyretin is primarily produced by the liver and circulates in blood as a tetramer. The retinal epithelium also secretes transthyretin, which is secreted to the vitreous humor of the eye. Because of mutations or aging, transthyretin can dissociate into amyloidogenic monomers triggering amyloid fibril formation. The deposition of transthyretin amyloid fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryo-electron microscopy, here we determined the structures of amyloid fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found that fibrils from both tissues share a consistent structural conformation, similar to the previously described structure of cardiac fibrils from an individual with the same genotype, but different from the fibril structure obtained from the vitreous humor. Our study hints to a uniform fibrillar architecture across different tissues within the same individual, only when the source of transthyretin is the liver. Moreover, this study provides the first description of ATTR fibrils from the nerves of a patient and enhances our understanding of the role of deposition site and protein production site in shaping the fibril structure in ATTRv-V30M amyloidosis.

biophysics↗

bioRxiv2024

Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant

ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may result from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as cardiomyopathy, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from multisystem organ involvement. Over 220 different mutational variants of transthyretin have been identified, many of them being linked to specific disease symptoms. Yet, the role of these mutations in explaining differential disease manifestations remains unclear. Using cryo-electron microscopy, here we structurally characterized fibrils from the heart and the liver of an ATTRv patient carrying the V122{Delta} mutation, which is predominantly associated with polyneuropathy. Our results show that these fibrils are polymorphic, presenting as both single and double filaments. Our study alludes to a structural connection contributing to phenotypic variation in ATTR amyloidosis, as polymorphism in ATTR fibrils may manifest in patients with predominantly polyneuropathic phenotypes. SignificanceATTR amyloidosis is a systemic, clinically diverse disease that results in organ failure due to the accumulation of transthyretin amyloid fibrils. ATTR patients present with varied symptoms, yet the root of this phenotypic heterogeneity remains unclear. Previous studies suggest an association between phenotype and fibril structure polymorphism. Here we describe the cryo-electron microscopy structure of variant transthyretin amyloid fibrils associated with a predominantly polyneuropathy phenotype. We have found polymorphism within these fibrils, a phenomenon we have thus far only observed in polyneuropathic associated transthyretin mutations. Our results signify an association between fibril structure and phenotype in ATTR amyloidosis.

molecular biology↗