Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant

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

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Multi-organ structural homogeneity of amyloid fibrils in ATTRv-T60A amyloidosis patients, revealed by Cryo-EM

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

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Assessing amyloid fibrils and amorphous aggregates: A review

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 143725 - 143725

Published: May 1, 2025

Protein misfolding and aggregation play a central role in the progression of neurodegenerative diseases such as Alzheimer's Parkinson's. These aggregates manifest either structured amyloid fibrils enriched β-sheet conformations or irregular amorphous with diverse morphologies. Understanding their formation, structure, behavior is critical for deciphering disease mechanisms developing targeted diagnostics therapeutics. This review presents an integrated overview both conventional advanced techniques used to detect, distinguish, structurally characterize these protein aggregates. It covers range spectroscopic spectrometric tools, fluorescence, Raman, mass spectrometry that facilitate aggregate identification. Microscopy methods, including atomic force electron microscopy, are highlighted morphological analysis. The also discusses situ detection strategies using fluorescent dyes, conformation-specific antibodies, enzymatic reporters, real-time imaging. Separation methods like centrifugation, electrophoresis, chromatography outlined alongside structural analysis tools X-ray diffraction. Furthermore, growing utility computational approaches artificial intelligence predicting propensities integrating biological data emphasized. By critically evaluating each method's capabilities limitations, this provides practical forward-looking resource researchers studying complex landscape aggregation.

Language: Английский

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The causative role of amyloidosis in the cardiac complications of Alzheimer's disease: a comprehensive systematic review

The Journal of Physiology, Journal Year: 2025, Volume and Issue: unknown

Published: May 5, 2025

Abstract Alzheimer's disease (AD), the leading cause of dementia, is characterised by cerebral amyloid‐beta (Aβ) and tau deposition, impairing cognition. While cardiovascular diseases exacerbate AD, reverse association underappreciated. This systematic review examined clinical experimental studies that explored cardiogenic dementia hypothesis mechanisms which amyloidosis in AD contributes to complications. A PubMed, Ovid Embase/Medline, CINAHL conducted August 2024 identified 252 meeting selection criteria. Evidence links hypoperfusion from cardiac arrest, heart failure, or orthostatic hypotension pathology, while atherosclerosis hypertension drive neurodegeneration amyloidosis. Vascular scoring tools, such as Framingham Risk Score, may predict an individual's risk cognitive impairment. Cardiac correlated with ECG abnormalities, aortic valve calcification, cardiomyopathy atrial fibrillation. Aβ peptides AD‐related genes fibrosis, negative inotropy rate changes, reduce nitric oxide‐mediated vasodilatation, increase oxidative stress. Preclinical revealed β‐secretase impacts repolarisation interfering delayed rectifier current, although evidence for arrhythmogenesis remains conflicting. autonomic dysregulation, particularly parasympathetic dysfunction, predisposes arrhythmias. Additionally, hypercortisolaemia observed has been associated increased arterial stiffness. Diminished melatonin levels were also linked endothelial mitochondrial dysfunction. enhances our understanding how amyloidosis, endocrinopathy contribute complications paving way research into targeted therapies. image

Language: Английский

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ATTRv-V30M amyloid fibrils from heart and nerves exhibit structural homogeneity

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

Published: Oct. 17, 2024

Language: Английский

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ATTRv-V30M Type A amyloid fibrils from the heart and nerves exhibit structural homogeneity.

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

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Does the structure of transthyretin amyloid fibrils vary depending on the organ of accumulation?

Structure, Journal Year: 2024, Volume and Issue: 32(12), P. 2181 - 2182

Published: Dec. 1, 2024

Language: Английский

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