Cryo-EM reveals that cardiac IGLV6-derived AL fibrils can be polymorphic DOI Open Access
Parker Bassett, Binh A. Nguyen, Virender Singh

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 5, 2024

ABSTRACT AL amyloidosis is a systemic disease caused by the aggregation of free antibody light chains (LC) secreted aberrant plasma cell clones into bloodstream. These LC aggregates form amyloid fibrils that deposit in multiple organs, leading to organ failure and, ultimately, death. Investigating structural basis critical avenue for understanding biopathology amyloidosis. Structural insights fibril formation may reveal mechanisms driving deposition and inspire novel therapeutic strategies. Previous studies using cryo-electron microscopy have uncovered diverse structures extracted from patients, highlighting variability architecture. Here, we present cryo-EM structure cardiac patient with This reveals unique fold coexistence morphologies, including single- double-protofilament forms. Notably, some these exhibit an uncommon rotational symmetry, raising intriguing questions about governing evolution over time.

Language: Английский

Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis DOI Creative Commons
Binh A. Nguyen, Virender Singh, Shumaila Afrin

et al.

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: July 27, 2024

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

Language: Английский

Citations

5
Multi-organ structural homogeneity of amyloid fibrils in ATTRv-T60A amyloidosis patients, revealed by Cryo-EM DOI Creative Commons
María del Carmen Fernández‐Ramírez, Binh A. Nguyen, Preeti Singh

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

ATTR amyloidosis is a degenerative disorder characterized by the systemic deposition of protein transthyretin. These amyloid aggregates transthyretin (ATTR) can deposit in different parts body causing diverse clinical manifestations. Our laboratory aims to investigate potential relationship between genotypes, organ deposition, phenotypes, and structure fibrils. Using cryo-electron microscopy, we have recently described how neuropathic related mutations ATTRv-I84S ATTRv-V122∆ drive structural polymorphism

Language: Английский

Citations

3
ATTRv-V30M Type A amyloid fibrils from the heart and nerves exhibit structural homogeneity. DOI Creative Commons
Binh A. Nguyen, Shumaila Afrin, Anna Yakubovska

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

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

Language: Английский

Citations

1
Cryo-EM reveals that cardiac IGLV6-derived AL fibrils can be polymorphic DOI Open Access
Parker Bassett, Binh A. Nguyen, Virender Singh

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 5, 2024

ABSTRACT AL amyloidosis is a systemic disease caused by the aggregation of free antibody light chains (LC) secreted aberrant plasma cell clones into bloodstream. These LC aggregates form amyloid fibrils that deposit in multiple organs, leading to organ failure and, ultimately, death. Investigating structural basis critical avenue for understanding biopathology amyloidosis. Structural insights fibril formation may reveal mechanisms driving deposition and inspire novel therapeutic strategies. Previous studies using cryo-electron microscopy have uncovered diverse structures extracted from patients, highlighting variability architecture. Here, we present cryo-EM structure cardiac patient with This reveals unique fold coexistence morphologies, including single- double-protofilament forms. Notably, some these exhibit an uncommon rotational symmetry, raising intriguing questions about governing evolution over time.

Language: Английский

Citations

0