Protofibril–Fibril Interactions Inhibit Amyloid Fibril Assembly by Obstructing Secondary Nucleation

Hasecke, Filip; Niyangoda, Chamani; Borjas, Gustavo; Pan, Jianjun; Matthews, Garrett; Muschol, Martin; Hoyer, Wolfgang

doi:10.1002/anie.202010098

Cited by 27 publications

(30 citation statements)

References 32 publications

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“…Furthermore, computational simulation studies have identified a conversion pathway between prefibrillar and fibrillar forms [29,30]. In addition to this, secondary nucleation, which has recently attracted much attention as an important reaction to proliferate amyloid fibrils [11,12,31], is predicted an alternate mechanism. In this case, the surface of prefibrillar aggregates is conceived to function as a reaction field for secondary nucleation, and prefibrillar aggregates themselves then eventually dissociate to supply peptides for the growth of more stable amyloid fibrils.…”

Section: Discussionmentioning

confidence: 99%

Pathway Dependence of the Formation and Development of Prefibrillar Aggregates in Insulin B Chain

et al. 2022

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Amyloid fibrils have been an important subject as they are involved in the development of many amyloidoses and neurodegenerative diseases. The formation of amyloid fibrils is typically initiated by nucleation, whereas its exact mechanisms are largely unknown. With this situation, we have previously identified prefibrillar aggregates in the formation of insulin B chain amyloid fibrils, which have provided an insight into the mechanisms of protein assembly involved in nucleation. Here, we have investigated the formation of insulin B chain amyloid fibrils under different pH conditions to better understand amyloid nucleation mediated by prefibrillar aggregates. The B chain showed strong propensity to form amyloid fibrils over a wide pH range, and prefibrillar aggregates were formed under all examined conditions. In particular, different structures of amyloid fibrils were found at pH 5.2 and pH 8.7, making it possible to compare different pathways. Detailed investigations at pH 5.2 in comparison with those at pH 8.7 have suggested that the evolution of protofibril-like aggregates is a common mechanism. In addition, different processes of evolution of the prefibrillar aggregates have also been identified, suggesting that the nucleation processes diversify depending on the polymorphism of amyloid fibrils.

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Section: Discussionmentioning

confidence: 99%

Pathway Dependence of the Formation and Development of Prefibrillar Aggregates in Insulin B Chain

et al. 2022

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“…In addition, because the energy barrier for formation of the amorphous aggregate is much lower than that for fibril formation, the amorphous aggregates are rapidly formed without a lag time. , Thus, the amorphous aggregates are preferentially formed under shaking at higher salt concentrations regardless of their lower stability compared with the fibrils, corresponding to the amorphous-region in the phase diagram. As Hasecke and co-workers reported, the kinetically trapped oligomeric aggregates can work as an inhibitor of fibril formation. Therefore, the progress of the amorphous-aggregate formation prevents monomers from forming fibrils.…”

Section: Resultsmentioning

confidence: 80%

Half-Time Heat Map Reveals Ultrasonic Effects on Morphology and Kinetics of Amyloidogenic Aggregation Reaction

Nakajima

Toda

Yamaguchi

et al. 2021

ACS Chem. Neurosci.

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Ultrasonication has been recently adopted in amyloid-fibril assays because of its ability to accelerate fibril formation, being promising in the early stage diagnosis of amyloidoses in clinical applications. Although applications of this technique are expanding in the field of protein science, its effects on the aggregation reactions of amyloidogenic proteins are poorly understood. In this study, we comprehensively investigated the morphology and structure of resultant aggregates, kinetics of fibril formation, and seed-detection sensitivity under ultrasonication using β 2 -microglobulin and compared these characteristics under shaking, which has been traditionally adopted in amyloid-fibril assays. To discuss the ultrasonic effects on the amyloid-fibril formation, we propose the half-time heat map, which describes the phase diagram of the aggregation reaction of amyloidogenic proteins. The experimental results show that ultrasonication greatly promotes fibril formation, especially in dilute monomer solutions, induces short-dispersed fibrils, and is capable of detecting ultra-trace-concentration seeds with a detection limit of 10 fM. Furthermore, we indicate that ultrasonication highly alters the energy landscape of an aggregation reaction due to the effect of ultrasonic cavitation. These insights contribute not only to our understanding of the effects of agitation on amyloidogenic aggregation reactions but also to their effective application in the clinical diagnosis of amyloidoses.

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“…To determine the formation of intracellular assemblies, confocal laser scanning microscopy (CLSM) was employed to label β‐sheet structures in assemblies with ThT staining. [ 29 ] Here, 2p was selected to verify the dynamic assembly and disassembly processes in cells. It should be noted that there were intrinsic β‐sheet structures in living HeLa cells, which emitted basal fluorescence after ThT staining ( Figure A).…”

Section: Resultsmentioning

confidence: 99%

Bioorthogonal Disassembly of Tetrazine Bearing Supramolecular Assemblies Inside Living Cells

Song

Zhao

et al. 2021

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Supramolecular assemblies are an emerging class of nanomaterials for drug delivery systems (DDS), while their unintended retention in the biological milieu remains largely unsolved. To realize the prompt clearance of supramolecular assemblies, the bioorthogonal reaction to disassemble and clear the supramolecular assemblies within living cells is investigated here. A series of tetrazine‐capped assembly precursors which can self‐assemble into nanofibers and hydrogels upon enzymatic dephosphorylation are designed. Such an enzyme‐instructed supramolecular assembly process can perform intracellularly. The time‐dependent accumulation of assemblies elicits oxidative stress and induces cellular toxicity. Tetrazine‐bearing assemblies react with trans‐cyclooctene derivatives, which lead to the disruption of π–π stacking and induce disassembly. In this way, the intracellular self‐assemblies disassemble and are deprived of potency. This bioorthogonal disassembly strategy leverages the biosafety aspect in developing nanomaterials for DDSs.

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Protofibril–Fibril Interactions Inhibit Amyloid Fibril Assembly by Obstructing Secondary Nucleation

Cited by 27 publications

References 32 publications

Pathway Dependence of the Formation and Development of Prefibrillar Aggregates in Insulin B Chain

Pathway Dependence of the Formation and Development of Prefibrillar Aggregates in Insulin B Chain

Half-Time Heat Map Reveals Ultrasonic Effects on Morphology and Kinetics of Amyloidogenic Aggregation Reaction

Bioorthogonal Disassembly of Tetrazine Bearing Supramolecular Assemblies Inside Living Cells

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