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

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.

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

Published: March 9, 2024

Abstract 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 an unprecedented structural variability 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. One-Sentence Summary: Wild-type

Language: Английский

Citations

3
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.

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

Published: March 10, 2024

ATTR amyloidosis is a relentlessly progressive disease caused by the misfolding and systemic accumulation of amyloidogenic transthyretin 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 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 reveals potential diagnostic therapeutic target.

Language: Английский

Citations

3
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
Conformational Dynamics of an Amyloidogenic Intermediate of Transthyretin: Implications for Structural Remodeling and Amyloid Formation DOI
Benjamin I. Leach, James A. Ferguson, Gareth J. Morgan

et al.

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(16), P. 168673 - 168673

Published: June 21, 2024

Language: Английский

Citations

3
Molecular basis for non-invasive diagnostics of cardiac amyloids using bone tracers DOI Creative Commons
Emily Lewkowicz,

Shobini Jayaraman,

Olga Gursky

et al.

Biomaterials Science, Journal Year: 2024, Volume and Issue: 12(17), P. 4275 - 4282

Published: Jan. 1, 2024

Amyloid diseases including Alzheimer's, Parkinson's and over 30 others are incurable life-threatening disorders caused by abnormal protein deposition as fibrils in various organs. Cardiac amyloidosis is particularly challenging to diagnose treat. Identification of the fibril-forming protein, which heart usually amyloid transthyretin (ATTR) or immunoglobulin light chain (AL), paramount treatment. A transformative non-invasive diagnostic modality imaging using technetium-labeled pyrophosphate diphosphonate bone tracers, 99mTc-PYP/DPD/HMDP. For unknown reasons, these tracers show preferential uptake ATTR deposits. The tracer-binding moiety potentially involves and/or amyloid-associated calcific We propose that, like bone, chelate surface-bound Ca2+ amyloid. In high-affinity sites, coordinated pairs acidic residues. To identify such residues on amyloids, we harnessed atomic structures patient-derived cardiac amyloids determined cryogenic electron microscopy since 2019. These help explain why most but not all deposits 99mTc-PYP/DPD/HMDP radiotracers, while AL opposite true. Moreover, fibril greater microcalcification observed vs. findings may aid diagnostics therapeutic targeting relevant other amyloids.

Language: Английский

Citations

3
O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology DOI Creative Commons
Aaron T. Balana, Anne‐Laure Mahul‐Mellier, Binh A. Nguyen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 7, 2023

ABSTRACT The process of amyloid fibril formation remains one the primary targets for developing diagnostics and treatments several neurodegenerative diseases (NDDs). Amyloid-forming proteins such α-Synuclein Tau, which are implicated in pathogenesis Alzheimer’s Parkinson’s disease, can form different types structure, or strains, that exhibit distinct structures, toxic properties, seeding activities, pathology spreading patterns brain. Therefore, understanding molecular structural determinants contributing to strains their features could open new avenues disease-specific therapies. In this work, we report O-GlcNAc modification monomers results with core as revealed by Cryo-EM, diminished activity seeding-based neuronal rodent models disease. Although mechanisms underpinning neutralization modified fibrils remain unclear, our vitro mechanistic studies indicate heat shock interactions inhibit activity, suggesting may alter interactome ways lead reduce vivo. Our show post-translational modifications, modification, key pathogenicity. These findings have significant implications how investigate target amyloids brain possibly explain lack correlation between burden neurodegeneration cognitive decline some subtypes NDDs.

Language: Английский

Citations

8
Amyloid and collagen templates in aortic valve calcification DOI

Shobini Jayaraman,

Navneet Narula, Jagat Narula

et al.

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(11), P. 1010 - 1019

Published: June 5, 2024

Language: Английский

Citations

2
ATTRv-V30M amyloid fibrils from heart and nerves exhibit structural homogeneity DOI
Binh A. Nguyen, Shumaila Afrin, Anna Yakubovska

et al.

Structure, Journal Year: 2024, Volume and Issue: 32(12), P. 2244 - 2250.e3

Published: Oct. 17, 2024

Language: Английский

Citations

2
Characterization of an amyloidogenic intermediate of transthyretin by NMR relaxation dispersion DOI Creative Commons
Benjamin I. Leach, James A. Ferguson, Gareth J. Morgan

et al.

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

Published: Feb. 21, 2024

Abstract The aggregation pathway of transthyretin (TTR) proceeds through rate-limiting dissociation the tetramer and partial misfolding monomers, which assemble into amyloid structures a downhill polymerization mechanism. structural features aggregation-prone monomeric intermediate are poorly understood. Characterization amyloidogenic intermediates is challenging due to their propensity aggregate at concentrations necessary for studies. NMR relaxation dispersion offers unique opportunity characterize these when they exchange on favorable timescales with NMR-visible ground states. To transitions associated dissociation, we have analyzed ground-state chemical shift differences between native an engineered monomer in critical F87 side chain replaced by glutamate. secondary structure overall fold F87E similar that except β-strand H. This strand populates two conformations, where it either docked protein core or displaced from edge β-sheet formed β-strands D, A, G, H (DAGH β-sheet) dynamically disordered. Chemical derived analysis 1 H/ 15 N single, double zero quantum data provide insights low-lying excited state exchanges rate 3800 s -1 . Disruption subunit interfaces TTR leads destabilization strands both β-sheets monomer. Conformational fluctuations propagated entire hydrogen bonding network DAGH β-sheet, inner H, forms strong dimer interface tetramer, outer D unfolded fibrils. Fluctuations also AB loop weak EF helix, undergoes remodeling conformational regions enhanced acidic pH formation most favorable. dynamics predispose progression

Language: Английский

Citations

1
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