Real-Time Observation of the Interaction between Thioflavin T and an Amyloid Protein by Using High-Sensitivity Rheo-NMR

Iwakawa, Naoto; Morimoto, Daichi; Walinda, Erik; Kawata, Yasushi; Shirakawa, Masahiro; Sugase, Kenji

doi:10.3390/ijms18112271

Cited by 10 publications

(20 citation statements)

References 19 publications

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“…Because the secondary structure of Aβ determines its cytotoxicity, changes in CSF flow due to aging or disorders , may increase toxicity by altering Aβ conformation. Furthermore, flow increases intermolecular alignment and decreases the energy barrier for nucleation, the molecular effects of which have been confirmed via the flow-dependent modulation of nucleation, fibril growth, and other intra- and intermolecular processes of Aβ and other biological macromolecules. − However, these studies examined Aβ in the absence of a cell membrane ( i.e. , stirring or shaking bath; Figure ) and did not evaluate the role of flowing condition on Aβ–lipid interactions and flow-triggered cytotoxicity.…”

mentioning

confidence: 99%

Promoted Aggregation of Aβ on Lipid Bilayers in an Open Flowing System

Iida

Abe

Nochi

et al. 2021

J. Phys. Chem. Lett.

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Self-assembly of amyloid-β (Aβ) peptides in nonequilibrium, flowing conditions is associated with pathogenesis of Alzheimer’s disease. We examined the role of biologically relevant, nonequilibrium, flowing conditions in the desorption, diffusion, and integration of Aβ-lipid assemblies at the membrane surface using a microchannel connected with microsyringes. A 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayer was formed on a glass substrate and incubated in Aβ solution under either a quiescent condition (no flow) or flowing condition for 24 h. Although dot-like aggregates (<1 μm) comprising Aβ fibrils formed on the DMPC membrane under the quiescent condition, larger plaque-like aggregates formed under the flowing condition, suggesting that nonequilibrium continuous flow governs the cytotoxicity of Aβ species. We propose that Aβ adsorption on the membrane surface involves spontaneous desorption of Aβ-lipid to form self-assembling aggregates, with this accelerated by surface shear forces. These findings suggest that nonequilibrium, flowing conditions influence inter/intra-molecular Aβ-fibril formation to trigger formation of amyloid plaques.

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confidence: 99%

Promoted Aggregation of Aβ on Lipid Bilayers in an Open Flowing System

Iida

Abe

Nochi

et al. 2021

J. Phys. Chem. Lett.

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“…Shear stress has been reported to induce fibril aggregation of the whey protein beta-lactoglobulin 29 , 33 . A rheo NMR study of superoxide dismutase 1 (SOD1) showed that shear stress can induce the formation of amyloid fibrils from SOD1 monomers, while under static conditions there is no change in the monomer state 34 . Therefore, it is possible that shear stress caused by pipetting induced the transition to the amorphous aggregate state.…”

Section: Discussionmentioning

confidence: 99%

Non-coding RNA suppresses FUS aggregation caused by mechanistic shear stress on pipetting in a sequence-dependent manner

Hamad

Yoneda

et al. 2021

Sci Rep

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Fused in sarcoma/translocated in liposarcoma (FUS/TLS) is a multitasking RNA/DNA binding protein. FUS aggregation is implicated in various neurodegenerative diseases. RNA was suggested to modulate phase transition of FUS. Here, we found that FUS transforms into the amorphous aggregation state as an instant response to the shear stress caused by usual pipetting even at a low FUS concentration, 100 nM. It was revealed that non-coding RNA can suppress the transformation of FUS into aggregates. The suppressive effect of RNA on FUS aggregation is sequence-dependent. These results suggested that the non-coding RNA could be a prospective suppressor of FUS aggregation caused by mechanistic stress in cells. Our finding might pave the way for more research on the role of RNAs as aggregation inhibitors, which could facilitate the development of therapies for neurodegenerative diseases.

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“…In addition to crowding effects, other factors may contribute to protein aggregation inside living cells, including chemical (e.g., decreased pH , ) and mechanical (e.g., shear or stretch − ) factors. Indeed, aggregation of SOD1 has a strong dependence on pH, and we previously observed aggregate formation of SOD1 under dilute experimental conditions applying shear flow . To further understand the real conformational behavior of SOD1 inside living cells, R 2 relaxation dispersion measurements in living cells should be used to acquire information on the off-pathway transitions of SOD1 in situ .…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, aggregation of SOD1 has a strong dependence on pH, 92 and we previously observed aggregate formation of SOD1 under dilute experimental conditions applying shear flow. 93 To further understand the real conformational behavior of SOD1 inside living cells, R 2 relaxation dispersion measurements in living cells should be used to acquire information on the off-pathway transitions of SOD1 in situ.…”

mentioning

confidence: 99%

Transient Diffusive Interactions with a Protein Crowder Affect Aggregation Processes of Superoxide Dismutase 1 β-Barrel

et al. 2021

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Aggregate formation of superoxide dismutase 1 (SOD1) inside motor neurons is known as a major factor in onset of amyotrophic lateral sclerosis. The thermodynamic stability of the SOD1 β-barrel has been shown to decrease in crowded environments such as inside a cell, but it remains unclear how the thermodynamics of crowding-induced protein destabilization relate to SOD1 aggregation. Here we have examined the effects of a protein crowder, lysozyme, on fibril aggregate formation of the SOD1 β-barrel. We found that aggregate formation of SOD1 is decelerated even in mildly crowded solutions. Intriguingly, transient diffusive interactions with lysozyme do not significantly affect the static structure of the SOD1 β-barrel but stabilize an alternative excited "invisible" state. The net effect of crowding is to favor species off the aggregation pathway, thereby explaining the decelerated aggregation in the crowded environment. Our observations suggest that the intracellular environment may have a similar negative (inhibitory) effect on fibril formation of other amyloidogenic proteins in living cells. Deciphering how crowded intracellular environments affect aggregation and fibril formation of such disease-associated proteins will probably become central in understanding the exact role of aggregation in the etiology of these enigmatic diseases.

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Real-Time Observation of the Interaction between Thioflavin T and an Amyloid Protein by Using High-Sensitivity Rheo-NMR

Cited by 10 publications

References 19 publications

Promoted Aggregation of Aβ on Lipid Bilayers in an Open Flowing System

Promoted Aggregation of Aβ on Lipid Bilayers in an Open Flowing System

Non-coding RNA suppresses FUS aggregation caused by mechanistic shear stress on pipetting in a sequence-dependent manner

Transient Diffusive Interactions with a Protein Crowder Affect Aggregation Processes of Superoxide Dismutase 1 β-Barrel

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