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 M.; Chhapra, Farzeen; Saelices, Lorena

doi:10.1038/s42003-024-06588-6

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

Journal Article · Sat Jul 27 00:00:00 EDT 2024 · Communications Biology

DOI:https://doi.org/10.1038/s42003-024-06588-6· OSTI ID:2469853

^[1]; ^[1]; Afrin, Shumaila ^[1]; ^[1]; Pekala, Maja ^[1]; Ahmed, Yasmin ^[1]; Pedretti, Rose ^[1]; Canepa, Jacob ^[1]; ^[2]; Kluve-Beckerman, Barbara ^[3]; ^[1]; Chhapra, Farzeen ^[1]; ^[1]

University of Texas Southwestern Medical Center (UTSW), Dallas, TX (United States)
University of Texas Southwestern Medical Center, Dallas, TX (United States)
Indiana University School of Medicine, Indianapolis, IN (United States)

ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable. Previously, we found unique structural variabilities in cardiac amyloid fibrils from polyneuropathic ATTRv-I84S patients. In contrast, cardiac fibrils from five genotypically different patients with cardiomyopathy or mixed phenotypes are structurally homogeneous. To understand fibril structure’s impact on phenotype, it is necessary to study the fibrils from multiple patients sharing genotype and phenotype. Here we show the cryo-electron microscopy structures of fibrils extracted from four cardiomyopathic ATTRwt amyloidosis patients. Our study confirms that they share identical conformations with minimal structural variability, consistent with their homogenous clinical presentation. Our study contributes to the understanding of ATTR amyloidosis biopathology and calls for further studies.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2469853

Journal Information:: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 7; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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

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