Browsing by Author "Bassett, Parker"

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    Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant
    (bioRxiv, 2024-05-10) Ahmed, Yasmin; Nguyen, Binh An; Afrin, Shumaila; Singh, Virender; Evers, Bret; Singh, Preeti; Pedretti, Rose; Wang, Lanie; Bassett, Parker; Fernandez-Ramirez, Maria del Carmen; Pekala, Maja; Kluve-Beckerman, Barbara; Saelices, Lorena; Pathology and Laboratory Medicine, School of Medicine
    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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    ATTRv-V30M Type A amyloid fibrils from heart and nerves exhibit structural homogeneity
    (bioRxiv, 2024-05-14) Nguyen, Binh An; Afrin, Shumaila; Yakubovska, Anna; Singh, Virender; Alicea, Jaime Vaquer; Kunach, Peter; Singh, Preeti; Pekala, Maja; Ahmed, Yasmin; Fernandez-Ramirez, Maria del Carmen; Cabrera Hernandez, Luis O.; Pedretti, Rose; Bassett, Parker; Wang, Lanie; Lemoff, Andrew; Villalon, Layla; Kluve-Beckerman, Barbara; Saelices, Lorena; Pathology and Laboratory Medicine, School of Medicine
    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.