Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis

Nguyen, Binh An; Singh, Virender; Afrin, Shumaila; Singh, Preeti; Pekala, Maja; Ahmed, Yasmin; Pedretti, Rose; Canepa, Jacob; Lemoff, Andrew; Kluve-Beckerman, Barbara; Wydorski, Pawel; Chhapra, Farzeen; Saelices, Lorena

doi:10.1101/2024.03.08.582936

Cited by 3 publications

(23 citation statements)

References 53 publications

(93 reference statements)

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“…The early cryo-EM studies of ATTR fibrils revealed a unique structure conformation, made of two fragments of transthyretin and forming a polar channel that runs through the fibril 16 . We and others have found that the amyloid fibrils from multiple ATTRwt amyloidosis patients are structurally homogenous, which is consistent with their more uniform disease presentation with cardiomyopathy 16,17 . In contrast, our recent study on ATTR fibrils from polyneuropathic ATTRI84S patients reveals an unprecedented structural polymorphism 18 .…”

Section: Introductionsupporting

confidence: 86%

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

Ahmed,

Nguyen,

Afrin

et al. 2024

Preprint

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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 stem from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as a cardiomyopathy phenotype, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from secondary organ involvement. Over 130 different mutational variants of transthyretin have been identified, many of them being linked to specific disease symptoms. Yet, the role of these mutations in the differential disease manifestation remains elusive. Using cryo-electron microscopy, here we structurally characterized fibrils from the heart of an ATTRv patient carrying the V122Δ mutation, 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.

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Section: Introductionsupporting

confidence: 86%

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

Ahmed,

Nguyen,

Afrin

et al. 2024

Preprint

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“…A. Nguyen et al, 2024). Despite the high structural homogeneity of ATTR fibrils, we and others have found structural variations, or polymorphism , in ATTR fibrils.…”

Section: Introductionmentioning

confidence: 94%

“…ATTR fibril polymorphism was found at two levels: the number of protofilaments and the conformation of the polar pocket. With the exception of fibrils from an ATTRv-V122Δ patient (Yasmin et al, 2024), all cardiac ATTR fibrils are found to have one single protofilament (Binh An Nguyen et al, 2024; B. A.…”

Section: Introductionmentioning

confidence: 99%

“…A. Nguyen et al, 2024; Schmidt et al, 2019; Steinebrei et al, 2023; Steinebrei et al, 2022). The exceptions, ATTRv-V122Δ cardiac fibrils from a neuropathic patient, contained one or two protofilaments; with single fibrils being the most represented population (78%).…”

Section: Introductionmentioning

confidence: 99%

“…A. Nguyen et al, 2024; Schmidt et al, 2019; Steinebrei et al, 2023; Steinebrei et al, 2022). In contrast, this segment can adopt multiple conformations in cardiac ATTRv-I84S fibrils (B.…”

Section: Introductionmentioning

confidence: 99%

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Multi-organ structural homogeneity of amyloid fibrils in ATTRv-T60A amyloidosis patients, revealed by Cryo-EM

Fernandez-Ramirez,

Nguyen,

Singh

et al. 2024

Preprint

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ATTR amyloidosis is a degenerative disorder characterized by the systemic deposition of the protein transthyretin. These amyloid aggregates of transthyretin (ATTR) can deposit in different parts of the body causing diverse clinical manifestations. Our laboratory aims to investigate a potential relationship between the different genotypes, organ of deposition, clinical phenotypes, and the structure of ATTR fibrils. Using cryo-electron microscopy, we have recently described how the neuropathic related mutations ATTRv-I84S and ATTRv-V122Δ can drive structural polymorphism in ex vivo fibrils. Here we question whether the mutation ATTRv-T60A, that commonly triggers cardiac and neuropathic symptoms, has a similar effect. To address this question, we extracted and determined the structure of ATTR-T60A fibrils from multiple organs (heart, thyroid, kidney, and liver) from the same patient and from the heart of two additional patients. We have found a consistent conformation among all the fibril structures, acquiring the closed-gate morphology previously found in ATTRwt and others ATTRv related to cardiac or mixed manifestations. The closed-gate morphology is composed by two segments of the protein that interact together forming a polar channel, where the residues glycine 57 to isoleucine 68 act as a gate of the polar cavity. Our study indicates that ATTR-T60A fibrils present in peripheral organs adopt the same structural conformation in all patients, regardless of the organ of deposition.

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

Nguyen,

Afrin,

Yakubovska

et al. 2024

Preprint

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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.

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Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis

Cited by 3 publications

References 53 publications

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

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

Multi-organ structural homogeneity of amyloid fibrils in ATTRv-T60A amyloidosis patients, revealed by Cryo-EM

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

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