Solid-state nuclear magnetic resonance in the structural study of polyglutamine aggregation

Biochemical Society Transactions, Год журнала: 2024, Номер 52(2), С. 719 - 731

Опубликована: Апрель 2, 2024

The aggregation of proteins into amyloid-like fibrils is seen in many neurodegenerative diseases. Recent years have much progress our understanding these misfolded protein inclusions, thanks to advances techniques such as solid-state nuclear magnetic resonance (ssNMR) spectroscopy and cryogenic electron microscopy (cryo-EM). However, multiple repeat-expansion-related disorders presented special challenges structural elucidation. This review discusses the role ssNMR analysis study aggregates associated with CAG repeat expansion disorders. In diseases, misfolding affect mutant expanded polyglutamine segments. most common disorder, Huntington's disease (HD), connected mutation huntingtin protein. Since discovery genetic causes for HD 1990s, steady has depended on integrative interdisciplinary use types techniques. heterogeneous dynamic features polyQ fibrils, particular those formed by N-terminal fragments, made challenging targets analysis. offered unique insights aspects aggregates. These include atomic-level structure core, but also measurements dynamics solvent accessibility non-core flanking domains fibrils' fuzzy coats. obtained shed new light pathogenic mechanisms behind this other

Язык: Английский

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Transient interactions between the fuzzy coat and the cross-β core of brain-derived Aβ42 filaments

Science Advances, Год журнала: 2025, Номер 11(3)

Опубликована: Янв. 15, 2025

Several human disorders, including Alzheimer’s disease (AD), are characterized by the aberrant formation of amyloid fibrils. In many cases, core is flanked disordered regions, known as fuzzy coat. The structural properties coats, and their interactions with environments, however, have not been fully described to date. Here, we generate conformational ensembles two brain-derived filaments Aβ42, corresponding respectively familial sporadic forms AD. Our approach, called metadynamic electron microscopy metainference (MEMMI), provides a characterization transient between coat cross-β filaments. These calculations indicate that AD less soluble than filaments, contributes solubilizing both types filament. results illustrate how approach can help analyze cryo-EM maps for

Язык: Английский

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Unveiling the Assembly Transition of Diphenylalanine and Its Analogs: from Oligomer Equilibrium to Nanocluster Formation

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Март 26, 2025

Peptide self-assembly is fundamental to various biological processes and holds significant potential for nanotechnology biomedical applications. Despite progress in understanding larger-scale assemblies, the early formation of low-molecular-weight oligomers remains poorly understood. In this study, we investigate aggregation behavior self-assembling diphenylalanine (FF) peptide its analogs. Utilizing single-nanopore analysis, detected characterized low-molecular-oligomer FF, N-tert-butoxycarbonyl-diphenylalanine (BocFF), fluorenylmethyloxycarbonyl-diphenylalanine (FmocFF), fluorenylmethyloxycarbonyl-pentafluoro-phenylalanine (Fmoc-F5-Phe) real time. This approach provided detailed insights into stages self-assembly, revealing dynamic kinetics oligomeric species. Analysis revealed that trimer key nucleus while dimer primary FmocFF Fmoc-F5-Phe aggregation, whereas both serve as nuclei BocFF. Mass photometry was employed track evolution these oligomers, transition from low- high-molecular-weight species, thereby elucidating intermediate phases process. Transmission electron microscopy Fourier transform infrared spectroscopy were further characterize final assembly states, offering high-resolution imaging morphological structures information on secondary structures. Based analyses, constructed a comprehensive graph correlates entire tested peptides across multiple scales. integrative provides holistic particularly toward mature supramolecular These findings shed light their pathways structural properties, advancing our

Язык: Английский

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MAPT mutations associated with familial tauopathies lead to formation of conformationally distinct oligomers that have cross‐seeding ability

Protein Science, Год журнала: 2024, Номер 33(9)

Опубликована: Авг. 15, 2024

Abstract The microtubule associated protein, tau, is implicated in a multitude of neurodegenerative disorders that are collectively termed as tauopathies. These characterized by the presence tau aggregates within brain afflicted individuals. Mutations MAPT gene encodes protein form genetic backdrop for familial forms tauopathies, such frontotemporal dementia (FTD), but molecular consequences alterations and their pathological effects unclear. We sought to investigate conformational properties three mutants: A152T, P301L, R406W, all FTD, compare them those native (WT‐Tau 2N4R). Our immunochemical analysis reveals mutants WT oligomers exhibit similar affinity conformation‐specific antibodies have distinct morphology secondary structure. Additionally, these possess different dye‐binding varying sensitivity proteolytic processing. results point variety among them. then tested ability mutant cross‐seed aggregation monomer. Using array experiments, we found cross‐seeding with leads formation conformationally unique oligomers. discussed this paper provide novel perspective on structural oligomeric 2N4R its mutant, along shedding some light behavior.

Язык: Английский

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Infections in the Etiology of Parkinson’s Disease and Synucleinopathies: A Renewed Perspective, Mechanistic Insights, and Therapeutic Implications

Journal of Parkinson s Disease, Год журнала: 2024, Номер unknown, С. 1 - 29

Опубликована: Сен. 25, 2024

Increasing evidence suggests a potential role for infectious pathogens in the etiology of synucleinopathies, group age-related neurodegenerative disorders including Parkinson’s disease (PD), multiple system atrophy and dementia with Lewy bodies. In this review, we discuss link between infections synucleinopathies from historical perspective, present emerging that supports link, address current research challenges focus on neuroinflammation. Infectious can elicit neuroinflammatory response modulate genetic risk PD related synucleinopathies. The mechanisms how might be linked as well overlap immune cellular pathways affected by virulent disease-related factors are discussed. Here, an important α-synuclein against is emerging. Critical methodological knowledge gaps addressed, provide new future perspectives to these gaps. Understanding neuroinflammation influence will essential development early diagnostic tools novel therapies.

Язык: Английский

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Transient interactions between the fuzzy coat and the cross-β core of brain-derived Aβ42 filaments

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 9, 2024

Abstract A wide range of human disorders, including Alzheimer’s disease (AD), are characterised by the aberrant formation amyloid fibrils. Amyloid fibrils filamentous structures characterized presence a highly-ordered cross-β core. In many cases, this core structure is flanked disordered regions, often referred to as fuzzy coat. The structural properties coats, and way in which they interact with their environments, however, have not been described full detail date. Here, we generated conformational ensembles two brain-derived filaments Aβ42, corresponding respectively familial sporadic forms AD. approach that used, called metadynamic electron microscopy metainference (MEMMI), enabled us provide characterization transient interactions between coat filaments. These calculations indicated AD less soluble than filaments, contributes increasing solubility both types filament. addition, analyzing deviations density maps from cryo-EM MEMMI ensembles, observed slowing down diffusion water sodium ions near surface offering insight into hydration dynamics results illustrate how can help analyse for characterisation

Язык: Английский

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Oligodendrocyte Dysfunction in Tauopathy: A Less Explored Area in Tau-Mediated Neurodegeneration

Cells, Год журнала: 2024, Номер 13(13), С. 1112 - 1112

Опубликована: Июнь 27, 2024

Aggregation of the microtubule-associated protein tau (MAPT) is hallmark pathology in a spectrum neurodegenerative disorders collectively called tauopathies. Physiologically, an inherent neuronal that plays important role assembly microtubules and axonal transport. However, disease-associated mutations this reduce its binding to microtubule components promote self-aggregation, leading formation tangles neurons. Tau also expressed oligodendrocytes, where it has significant developmental roles oligodendrocyte maturation myelin synthesis. Oligodendrocyte-specific pathology, form fibrils coiled coils, evident major tauopathies including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD). Multiple animal models tauopathy expressing mutant forms MAPT recapitulate oligodendroglial inclusions with potential cause degeneration/malfunction oligodendrocytes affecting sheath. Till now, mechanistic studies heavily concentrated on elucidating pathology. Therefore, more investigations are warranted comprehensively address tau-induced pathologies oligodendrocytes. The present review provides current knowledge available literature about intricate relations between health diseases.

Язык: Английский

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

Structure, Год журнала: 2024, Номер 32(12), С. 2244 - 2250.e3

Опубликована: Окт. 17, 2024

Язык: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 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.

Язык: Английский

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CapP mediates the structural formation of biofilm-specific pili in the opportunistic human pathogenBacillus cereus

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 27, 2024

SUMMARY Polymeric proteinaceous filaments are structural scaffolds that diversify the functionality of bacterial extracellular matrix. Here, we report a previously uncharacterized factor called bc1280 is exclusive to B. cereus group and indispensable for establishment biofilm lifestyle. We propose BC1280 an essential chaperone assembly filamentous platform tightly controls polymerization heteropili containing CalY TasA as major subunits in concentration-dependent manner. Additionally, modulates expression EPS via pathway activated by protease ECF-type sigma factor. The pilus biogenesis system described this work highlights complexity matrix introduces singular three-part structuration mechanism during formation maturation. Graphical abstract During process , TasA, CapP, serve main components, addition other factors, ensuring correctly assembles. three proteins produced processed signal peptidase SipW subsequently secreted through Sec unfolded conformation. At early stages, CapP initially present at low levels, associates with cell wall into ECM where it interacts CalY, facilitating folding initiating fibril growth. serves nucleator incorporating pilus, forming TasA-CalY heteropolymers. Once scaffold established, levels increase, stable complexes prevent its arrest filament

Язык: Английский

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