Structural Basis for Monoclonal Antibody Therapy for Transthyretin Amyloidosis DOI Creative Commons
Avijit Chakrabartty

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(9), P. 1225 - 1225

Published: Sept. 17, 2024

The disease of transthyretin (TTR) amyloidosis (ATTR) has been known since the 1960s, and during past 60 or so years, there a sustained period steady discoveries that have led to current model ATTR pathogenesis. More recent research achieved major advances in both diagnostics therapeutics for ATTR, which are having significant impact on patients today. Aiding these achievements remarkable ability cryo-electron microscopy (EM) determine high-resolution structures amyloid fibrils obtained from individual patients. Here, we will examine cryo-EM explore structural basis two monoclonal antibody therapies clinical trials, ALXN-2220 Coramitug, as well point out potential applications this approach other systemic diseases.

Language: Английский

O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology DOI Creative Commons
Aaron T. Balana, Anne‐Laure Mahul‐Mellier, Binh A. Nguyen

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(5), P. 646 - 655

Published: Feb. 12, 2024

Abstract Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer’s Parkinson’s disease, can form different fibril structures or strains with distinct toxic properties, seeding activities pathology. Understanding the determinants contributing to formation of amyloid features could open new avenues for developing disease-specific diagnostics therapies. Here we report that O-GlcNAc modification monomers results core structure, as revealed by cryogenic electron microscopy, diminished activity seeding-based neuronal rodent models disease. Although mechanisms underpinning neutralization O-GlcNAc-modified fibrils remain unclear, our vitro mechanistic studies indicate heat shock interactions inhibit their activity, suggesting may alter interactome ways lead reduce vivo. Our show posttranslational modifications, modification, key pathogenicity.

Language: Английский

Citations

28
Initiation of transthyretin aggregation at neutral pH by fluid agitation DOI Creative Commons
Irina Ritsch, H. Jane Dyson, Peter E. Wright

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(11)

Published: March 11, 2025

The transthyretin (TTR) tetramer, assembled as a dimer of dimers, transports thyroxine and retinol binding protein in blood plasma cerebrospinal fluid. Aggregation wild type (WT) or pathogenic variant TTR leads to amyloidosis, which is associated with neurodegenerative cardiac disease. trigger for aggregation under physiological conditions unknown. tetramer extremely stable at neutral pH, but via dissociation monomer misfolding can be induced vitro by lowering the pH. To elucidate factors that may cause we examined effect shear forces such those arise from fluid flow vascular system. Fluid were generated rapidly stirring solutions conical microcentrifuge tubes. Under agitation, formed β-rich aggregates fibrils rate was dependent upon concentration. lag time before onset agitation-induced increases total concentration increased, consistent mechanism first dissociates form either partially unfolds enter pathway reassociates tetramer. NMR spectra recorded various points during phase revealed growth an aggregation-prone intermediate trapped dynamically perturbed Enhanced conformational fluctuations weak dimer–dimer interface suggest loosening critical intersubunit contacts likely destabilizes agitated predisposes it toward dissociation. These studies provide insights into WT human near-physiological conditions.

Language: Английский

Citations

1
Structure-Based Probe Reveals the Presence of Large Transthyretin Aggregates in Plasma of ATTR Amyloidosis Patients DOI Creative Commons
Rose Pedretti, Lanie Wang, Anna Yakubovska

et al.

JACC Basic to Translational Science, Journal Year: 2024, Volume and Issue: 9(9), P. 1088 - 1100

Published: July 17, 2024

Amyloidogenic transthyretin (ATTR) amyloidosis is a relentlessly progressive disease caused by the misfolding and systemic accumulation of amyloidogenic into amyloid fibrils. These fibrils cause diverse clinical phenotypes, mainly cardiomyopathy and/or polyneuropathy. Little known about aggregation during development whether this has implications for diagnosis treatment. Using cryogenic electron microscopy structures mature ATTR fibrils, we developed peptide probe fibril detection. With probe, have identified previously unknown aggregated species in plasma patients with amyloidosis. are large, non-native, distinct from monomeric tetrameric transthyretin. Observations our study open many questions biology reveal potential diagnostic therapeutic target.

Language: Английский

Citations

5
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
Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant DOI Creative Commons
Yasmin Ahmed, Binh A. Nguyen, Shumaila Afrin

et al.

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

Published: May 10, 2024

Abstract ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in form amyloid fibrils into various organs. may stem from mutations variant (ATTRv) amyloidosis, or aging wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as cardiomyopathy phenotype, whereas ATTRv present polyneuropathy, cardiomyopathy, mixed, combination with many other symptoms deriving secondary organ involvement. Over 130 different mutational variants have been identified, them being linked to specific symptoms. Yet, role these differential manifestation remains elusive. Using cryo-electron microscopy, here we structurally heart an patient carrying V122Δ mutation, predominantly associated polyneuropathy. Our results show that are polymorphic, presenting both single and double filaments. study alludes structural connection contributing phenotypic variation polymorphism manifest patients polyneuropathic phenotypes.

Language: Английский

Citations

4
A computational approach to predict the effects of missense mutations on protein amyloidogenicity: A case study in hereditary transthyretin cardiomyopathy DOI

Ivan A Pyankov,

Valentin Gonay,

Yaroslav A. Stepanov

et al.

Journal of Structural Biology, Journal Year: 2025, Volume and Issue: 217(1), P. 108176 - 108176

Published: Feb. 9, 2025

Language: Английский

Citations

0
How is the Amyloid Fold Built? Polymorphism and the Microscopic Mechanisms of Fibril Assembly DOI Creative Commons
Liam D. Aubrey, Sheena E. Radford

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169008 - 169008

Published: Feb. 1, 2025

Language: Английский

Citations

0
Biomarkers in Subclinical Transthyretin Cardiac Amyloidosis DOI
Jaskeerat Gulati, Rose Pedretti, Nicholas Hendren

et al.

Current Heart Failure Reports, Journal Year: 2025, Volume and Issue: 22(1)

Published: Feb. 13, 2025

Language: Английский

Citations

0
Hereditary Transthyretin Cardiac Amyloidosis With the p.V142I Variant: Mechanistic Insights and Diagnostic Challenges DOI

Simon Vanhentenrijk,

Justin L. Grodin, Silvio Nunes Augusto

et al.

Circulation Heart Failure, Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

The most common form of hereditary transthyretin cardiac amyloidosis (hATTR-CA) in the United States and Kingdom is p.V142I variant. About 3% to 4% patients with African ancestry carry this genetic predisposition develop signs symptoms hATTR-CA. Nevertheless, clinical manifestations hATTR-CA appear only late fifth sixth decades life, despite its clear background. Imbalances native protein-stabilizing elementary breakdown cellular mechanisms are postulated as potential causes for affecting structural integrity myocardial fibril deposition. Noncoding variants, epigenetic environmental factors, well gut microbiome derangements may serve disease-modifying factors that feature detrimental amyloidogenic organ involvement impact disease severity. Organ amyloid deposition varies widely among different carriers a genotype-phenotype interdependence unpredictable phenotypic penetrance results variety patient outcomes. Cardiovascular biomarkers multimodality imaging identify initial involvement. These early clues through course offer window opportunity treatment onset cease progression alter prognosis. Identifying at-risk requires information on background probands their relatives. Initiatives reveal asymptomatic gene should be encouraged, it necessitates stringent follow-up immediate reduce burden heart failure hospitalization mortality

Language: Английский

Citations

0
Green tea polyphenol EGCG acts differentially on end-stage amyloid polymorphs of α-synuclein formed in different polyol osmolytes DOI

Santosh Devi,

Dushyant Kumar Garg, Rajiv Bhat

et al.

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Journal Year: 2025, Volume and Issue: unknown, P. 141073 - 141073

Published: April 1, 2025

Language: Английский

Citations

0